{"paper_id":"d92ff053-c804-4527-ba3e-e2d589484c44","body_text":"Vol.:(0123456789)\nhttps://doi.org/10.1007/s00210-025-04550-9\nREVIEW\nMolecular mechanisms underlying cyclophosphamide‑induced \novarian injury and protective strategies\nEhab E. Sharata1 · Taha Bakry1 · Habiba Gamal Atta1 · Habiba Atef Mohammed1 · Nazema Shaker Diab1 · \nRofaida Ashraf Atef1 · Roaa Sayed Hosney1 · Mahmoud Mohamed Omar2 · Ramadan A. M. Hemeida1\nReceived: 29 June 2025 / Accepted: 12 August 2025 / Published online: 12 September 2025 \n© The Author(s) 2025\nAbstract\nCyclophosphamide (CP) is an anti-cancer medication that also treats chronic inflammatory illnesses caused by the immune \nsystem. Although CP is widely used, it can occasionally have limited therapeutic efficacy due to its significant combined \ntoxicities. Ovarian damage caused by CP is a major problem for patients, and premature ovarian failure (POF) is a serious \nside effect of CP that commonly affects female patients. Mechanistic investigations have implicated oxidative stress, inflam-\nmatory responses, and apoptosis as critical components in the etiology of CP-induced POF, although the exact process by \nwhich this ovarian toxicity occurs remains unclear. After CP causes ovarian cells to generate proinflammatory cytokines, \nincluding interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB) is activated. The \nactivation of the NLRP3 inflammasome is the subsequent stage. In addition, Nrf2/HO-1 has been identified as an important \nsignaling pathway that mitigates oxidative stress in CP-induced POF due to its anti-inflammatory and antioxidative charac-\nteristics. Moreover, several recent studies highlighted the role of α-klotho deficiency in ovarian aging. Quercetin, resveratrol, \nberberine, curcumin, irbesartan, mirtazapine, sildenafil, atorvastatin, donepezil, cilostazol, moxibustion, LCZ696, buspirone, \nlevomilnacipran, melatonin, diosmin, and azilsartan are some of the agents that may protect against ovarian injury caused \nby CP, as shown in Graphical abstract. Our goal in writing this study is to provide a concise overview of the possible redox \nmolecular pathways that cause ovarian harm in CP and how to potentially ameliorate them. Finally, investigation into these \nmolecular pathways may pave the way for early ovarian damage relief and for the development of different agent strategies \nto alleviate CP-mediated POF.\n * Ehab E. Sharata \n ehab.essam@deraya.edu.eg\n Taha Bakry \n taha.bakry@deraya.edu.eg\n Habiba Gamal Atta \n habiba.gamal_1200070@student.deraya.edu.eg\n Habiba Atef Mohammed \n habiba.atef_1200071@student.deraya.edu.eg\n Nazema Shaker Diab \n nazema.shakr_1200272@student.deraya.edu.eg\n Rofaida Ashraf Atef \n rofida.ashraf_1200099@student.deraya.edu.eg\n Roaa Sayed Hosney \n roaa.sayed_1200110@student.deraya.edu.eg\n Mahmoud Mohamed Omar \n mahmoud.omar@deraya.edu.eg\n Ramadan A. M. Hemeida \n ramadan.hemeida@deraya.edu.eg\n1 Department of Pharmacology & Toxicology, Faculty \nof Pharmacy, Deraya University, Minia 61111, Egypt\n2 Department of Pharmaceutics and Pharmaceutical \nTechnology, Deraya University, 61519 Minia, Egypt\nNaunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nGraphical Abstract  \nSchematic illustration summarizing the molecular mechanisms underlying cyclophosphamide-induced ovarian injury and the protective strate -\ngies of various pharmacological and natural agents. The illustration demonstrates how the specified agents provide their protective effects by \ntargeting critical pathogenic pathways associated with cyclophosphamide-induced ovarian damage\nKeywords Cyclophosphamide · Premature ovarian failure · Apoptosis · Inflammation · Oxidative stress\nAbbreviations\nAFC  Antral follicle count\nAFSCs  Amniotic fluid stem cells\nAMH  Anti-Mullerian hormone\nAMPK  AMP-activated protein kinase\nANCA  Anti-neutrophil cytoplasmic antibody\nApaf-1  Apoptotic protease activating factor-1\nAP-1  Activator protein 1\nASC  Apoptosis-associated speck-like protein\nATV  Atorvastatin\nADSCs  Adipose-derived stem cells\nADMSCs  Adipose-derived mesenchymal stromal cells\nATP  Adenosine triphosphate\nBax  Bcl-2 associated X protein\nBBR  Berberine\nBcl-2  B-cell lymphoma 2\nBID  BH3 interacting domain death agonist\nBMSCs  Bone marrow mesenchymal stem cells\nBUS  Buspirone\nbFGF  Basic fibroblast growth factor\n1952 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nCAT   Catalase\nCNS  Central nervous system\nCOX-2  Cyclooxygenase-2\nCP  Cyclophosphamide\nCR  Curcumin\nDAMPs  Damage-associated molecular patterns\nDISC  Death-inducing signaling complex\nE2  Estradiol\nFDA  Food and Drug Administration\nFoxo3  Forkhead box O3\nFSH  Follicle-stimulating hormone\nGnRH  Gonadotropin-releasing hormone\nGC  Granulosa cell\nGPx  Glutathione peroxidase\nGSDMD  Gasdermin D\nGSH  Glutathione\nhAECs  Human amniotic epithelial cells\nHaCat  Human adult low calcium temperature cells\nHO-1  Heme oxygenase-1\nHRT  Hormone replacement therapy\nHUVEC  Human umbilical vein endothelial cell\nHUCMSCs  Human umbilical cord mesenchymal stem \ncells\nHGF  Hepatocyte growth factor\nIL-1β  Interleukin-1 beta\nIL-6  Interleukin-6\nIL-18  Interleukin-18\nIGF-1  Insulin-like growth factor-1\nIRAK  IL-1 receptor-associated kinase\nIRB  Irbesartan\nKEAP1  Kelch-like ECH-associated protein 1\nLCZ696  Sacubitril/valsartan (drug combination)\nLVM  Levomilnacipran\nMAPK  Mitogen-activated protein kinase\nMDA  Malondialdehyde\nmiRNA  MicroRNA\nMPO  Myeloperoxidase\nMSCs  Mesenchymal stem cells\nMTZ  MSCs\nmTOR  Mammalian target of rapamycin\nMyD88  Myeloid differentiation primary response 88\nNAD⁺  Nicotinamide adenine dinucleotide (oxi-\ndized form)\nNF-κB  Nuclear factor kappa-light-chain-enhancer \nof activated B cells\nNLRP3  NOD-like receptor family pyrin domain-\ncontaining 3 inflammasome\nNO  Nitric oxide\nNrf2  Nuclear factor erythroid 2-related factor 2\nONOO⁻  Peroxynitrite\nPGC1-α  Peroxisome proliferator-activated receptor \ngamma coactivator 1-alpha\nPI3K  Phosphatidylinositol 3-kinase\nPKB  Protein kinase B (also known as Akt)\nPOF  Premature ovarian failure\nPPAR-γ  Peroxisome proliferator-activated receptor \ngamma\nPTEN  Phosphatase and tensin homolog\nRES  Resveratrol\nRGC32  Regulator of cell cycle\nROS  Reactive oxygen species\nSIRT1  Silent information regulator-1 (sirtuin 1)\nSNRI  Serotonin and norepinephrine reuptake \ninhibitor\nSOD  Superoxide dismutase\nTIR  Toll-interleukin 1 receptor\nTIRAP  Toll-interleukin 1 receptor (TIR) domain-\ncontaining adaptor protein\nTLR4  Toll-like receptor 4\nTNF-α  Tumor necrosis factor-alpha\nTRAF6  TNF receptor-associated factor 6\nTRAM  Translocating chain-associated membrane \nprotein\nTRIF  TIR-domain-containing adapter-inducing \ninterferon-β\nTGF-β  Transforming growth factor\nVEGF-B  Vascular endothelial growth factor B\nWnt  Wingless-related integration site (signaling \npathway)\nIntroduction\nPremature ovarian failure (POF), also known as primary \novarian insufficiency or early menopause, is associated \nwith the cessation of ovarian Function before the age \nof 40 (Fu et al. 2021). The three criteria that character -\nize POF are amenorrhea persisting for a minimum of 4 \nmonths, diminished serum estradiol levels, and increased \nfollicle-stimulating hormone (FSH) serum levels, which \nmust exceed 40 IU/l in at least two samples taken several \nweeks apart (Mauri et al. 2020). Researchers estimate the \nincidence of POF to be 0.1% among women under 30 and \n1% among women under 40 who develop spontaneous \nPOF (Mauri et al. 2020 ). The aggregated prevalence of \nPOF reached 3.7%, as indicated by a recent meta-analysis \nexamining the global incidence of POF and early meno -\npause (Rahman and Panay 2021). Radiation therapy and \nchemotherapy employed in cancer treatment are among \nthe primary causes of POF. While chemotherapy and \nradiotherapy can improve cancer outcomes and promote \nprolonged lifespan in the young population (Zamanian \net al. 2024; Golmohammadi et al. 2023), problems such \nas ovarian failure may occur (Zhao et al. 2023). The sub -\nsequent chemotherapy drugs are strongly correlated with \n1953Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\novarian failure in clinical contexts: cyclophosphamide \n(CP), methotrexate, and cisplatin (Bhardwaj et al. 2023; \nChen et al. 2023; Li et al. 2023a). Ovarian function, char -\nacterized by rapid cellular turnover, may resemble tumor \ncells, as both are significant targets for chemotherapeutic \nagents. Ovarian primordial follicular cells lack regenera -\ntive capacity, and their loss leads to ovarian dysfunction, \nmanifesting as POF and infertility due to oocyte deple -\ntion, along with DNA damage and alterations in the func -\ntional and structural properties of oocytes (Pouladvand \net al. 2024).\nPharmacological and clinical applications \nof cyclophosphamide\nThe FDA indicates that CP is primarily used for the treat -\nment of malignant lymphomas in stages III and IV, as \nclassified by the Ann Arbor staging criteria. These may \nencompass Hodgkin and non-Hodgkin lymphoma, lym -\nphocytic lymphoma, small lymphocytic lymphoma, Burkitt \nlymphoma, and multiple myeloma (Mills et al. 2019; Xu \net al. 2013; Ansell 2015). In Hodgkin lymphoma, CP has \nbeen utilized in specific combination regimens, particularly \nfor patients who may be intolerant to traditional protocols \n(Ansell 2015). In non-Hodgkin lymphoma, CP is a core drug \nin several first-line regimens, especially B-cell lymphomas \n(Roschewski et al. 2014; Wang and Li 2021). High-dose CP \nis occasionally administered to individuals with refractory \nnon-Hodgkin lymphoma and may facilitate transition to stem \ncell transplantation. Low-dose metronomic CP (continuous \nlow dosing) has demonstrated potential for fragile individu-\nals with low-grade non-Hodgkin lymphoma, providing effec-\ntive results with reduced toxicity (Michot et al. 2020). CP \nhas demonstrated a clinically and statistically significant \nadvantage in diminishing disease activity in rheumatoid \narthritis, enhancing tender and swollen joint scores, and \nlowering the incidence of new or exacerbated joint erosions \n(Suarez-Almazor et al.  1996). CP attenuates the immune sys-\ntem by suppressing lymphocyte (T and B cell) growth, hence \ndiminishing inflammation and the autoimmune mechanisms \nassociated with rheumatic illnesses (Klein et al. 2018). Addi-\ntionally, CP is extensively utilized in the management of \nsystemic lupus erythematosus with significant organ involve-\nment (e.g., lupus nephritis), systemic vasculitis, including \nanti-neutrophil cytoplasmic antibody (ANCA)-associated \nvasculitis, systemic sclerosis with pulmonary involvement, \nand myopathies (Suarez-Almazor et al. 1996). CP in rheu -\nmatology may be administered orally or intravenously; intra-\nvenous pulse therapy (e.g., monthly infusions) is frequently \nemployed to mitigate cumulative toxicity (Suarez-Almazor \net al.  1996). It is typically utilized for a brief duration (3 \nto 6 months) to induce remission. Weaker drugs are then \nemployed for maintenance after disease control is attained \n(Hudson et al. 2020). In nephrology, CP is a powerful \nimmunosuppressive drug utilized for many severe kidney \ndisorders, predominantly those of autoimmune origin. In \nrapidly progressive glomerulonephritis, CP is a primary \ntherapeutic drug, frequently used alongside corticosteroids, \nto achieve remission in severe, life-threatening glomerulo -\nnephritis, including ANCA-associated vasculitis and Good-\npasture’s syndrome (Ponticelli et al. 2018). In neurology, \nCP functions as a second- or third-line immunosuppressant \nfor severe neuroimmunological disorders, especially when \nfirst-line therapies have proven ineffective. In CNS vasculi-\ntis, CP effectively induces remission in severe cases of pri -\nmary or secondary vasculitis involving the brain (Osen et al. \n2023; Nicole and Timothy 2024). In severe multiple sclero-\nsis, CP is used for refractory or aggressive demyelinating \ndisease. High-dose protocols can stabilize disease, reduce \nrelapses, and sometimes improve function (Osen et al. 2023; \nFereidan-Esfahani and Tobin 2021). It is considered in auto-\nimmune encephalitis when standard immunotherapies are \ninadequate, particularly if there is a progressive course or \nrelapse, and also used in neurosarcoidosis, some inflamma-\ntory neuropathies, and myasthenia gravis associated with \nimmune checkpoint inhibitors (Nicole and Timothy 2024).\nChemical properties and metabolism \nof cyclophosphamide\nCP ranks among the most efficacious anti-cancer drugs. CP \nremains employed as a chemotherapeutic agent in many \nmalignancies and autoimmune disorders (Souza et al. 2024). \nThe preliminary clinical trials of CP for cancer treatment \ncommenced in 1958, and in 1959, it was sanctioned as the \neighth cytotoxic anticancer agent by the FDA. CP functions \nas an inactive prodrug, necessitating enzymatic and chemi -\ncal activation; the resulting nitrogen mustard induces inter -\nstrand and intrastrand DNA crosslinks, which are respon -\nsible for its cytotoxic effects (Barnes et al. 2024). CP, in \ncombination with other antineoplastic agents, is utilized in \nthe treatment of several cancers, including breast, lymphoid, \nand pediatric malignancies. CP is employed in bone marrow \ntransplantation. Bone marrow suppression is the primary \nunfavorable effect of CP. Leukopenia, thrombocytopenia, \nand anemia commonly arise following the administration \nof high-dose CP (Scorer et al. 2023). Hemorrhagic cystitis \nis the primary sign of CP bladder toxicity; however, blad -\nder fibrosis and transitional or squamous cell carcinoma \nmay also develop. Hemorrhagic cystitis may present either \nacutely or chronically after chemotherapy treatment (Scorer \net al. 2023). The pharmacological precursor CP is metabo -\nlized by cytochrome P450 enzyme systems in the Liver, gen-\nerating 4-hydroxycyclophosphamide and aldophosphamide. \nGlycoproteins enable the active transport of these substances \ninto the cell. Aldophosphamide is then transformed into the \n1954 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nactive metabolites phosphoramide and acrolein. Acrolein \nand phosphamide trigger DNA breaks by chemically binding \nto DNA (Steinbrecht et al. 2020). 4-Hydroxycyclophospha-\nmide is enzymatically converted into 4-ketocyclophospha -\nmide, while aldehyde dehydrogenase converts aldophospha-\nmide into the innocuous carboxyphosphamide. Glutathione, \nan antioxidant, stabilizes carboxyphosphamide (Bignold \n2006; Iqubal et al. 2019). Increased levels of 4-hydroxycy-\nclophosphamide and carboxyethyl phosphamide have been \ndetected in the blood plasma of individuals receiving CP \ntherapy (Campagne et al. 2020). The primary metabolite, \nphosphoramide mustard, is a nitrogen mustard molecule \nconsidered the most therapeutically effective metabolite \nowing to its significant ability to induce DNA damage by \nintercalating between the two strands (Vredenburg et al. \n2015). The second metabolite, acrolein, is produced when \n4-hydroxy cyclophosphamide is activated to form active \nphosphoramide. It is a highly reactive metabolite consid -\nered the toxic element responsible for most of the deleteri -\nous effects of CP. It achieves this by impairing the body’s \nantioxidant defense systems and producing reactive oxygen \nspecies (ROS), including hydrogen peroxide and superoxide \nradicals. (Jeelani et al. 2017). ROS cause DNA and cellu -\nlar membrane damage, inhibit specific enzymes, and facili-\ntate lipid peroxidation, hence increasing the likelihood of \ninfertility (Sun et al. 2015). Females subjected to CP and \nacrolein may encounter ovarian failure and infertility (Detti \net al. 2013). The cytotoxicity of acrolein frequently restricts \nthe clinical utilization of CP. Acrolein has been linked to \noxidative stress generated by CP in animal models, which \ndisrupts biochemistry and physiology by producing free \nradicals (Wahlang et al. 2015). The metabolism of CP is \nsummarized in Fig.  1 (Steinbrecht et al. 2020).\nThe primary aim of this study is to elucidate the molec -\nular mechanisms underlying CP-induced ovarian injury, \nwith a focus on oxidative stress, inflammatory signaling, \nand apoptotic pathways, focusing on nuclear factor-kappa \nB (NF-κB), nuclear factor erythroid-2-related factor 2/heme \noxygenase-1 (Nrf2/HO-1), Toll-like receptor 4 (TLR4), \nnucleotide-binding oligomerization domain-like receptor \nfamily pyrin domain-containing 3 (NLRP3) inflammasome, \nsilent information regulator-1 (SIRT1), and other signaling \npathways involved in the pathogenesis of ovarian injury \ncaused by CP. Additionally, this review aims to critically \nevaluate various pharmacological and natural protective \nagents that have shown promise in experimental models to \nmitigate CP-mediated ovarian toxicity. Through integrating \nthese molecular insights and protective strategies, we seek to \nhighlight potential therapeutic targets and foster the develop-\nment of effective interventions to preserve ovarian function \nin female patients undergoing chemotherapy.\nFertility preservation strategies in clinical settings\nHormone replacement treatment\nHormone replacement treatment (HRT) is fundamental \nin the management of women with POF, including cases \ncaused by chemotherapy and other pharmacological drugs. \nThe principal objective of HRT is to substitute inadequate \novarian hormones, primarily estrogen, with or without pro -\ngestin, to re-establish physiological levels closer to those \nFig. 1  Metabolism of cyclophosphamide, including metabolic activation and inactivation pathways of cyclophosphamide (Steinbrecht et  al. \n2020)\n1955Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nobserved before menopause. HRT does not serve as a means \nof fertility preservation for chemotherapy-induced POF. \nHRT serves as a method for symptom management and a \nlong-term health strategy following ovarian injury (Cattoni \net al. 2021; Webber et al. 2017).\nHRT mitigates symptoms of estrogen shortage (such as \nhot flashes, vaginal dryness, sleeplessness, mood changes, \nand bone loss) and safeguards long-term health, mitigating \nthe risks of osteoporosis and cardiovascular disease, while \npreserving uterine health when the endometrium is intact \n(Laml et al. 2000). HRT (estrogen + progesterone) enhances \nendometrial thickness, promoting an optimal condition for \nembryo implantation during in vitro fertilization or rare \nspontaneous pregnancies. By mimicking normal hormonal \nvariations, HRT optimizes the endometrial cycle, facili -\ntating scheduled embryo transfer (Cartwright et al. 2016; \nDragojević-Dikić et al. 2009). In HRT, estrogen is deliv -\nered as transdermal estradiol (100 μg/day) or oral estradiol \n(2–4 mg/day) on days 1–26 of the cycle. Micronized pro -\ngesterone (200 mg/day) or medroxyprogesterone acetate \n(10 mg/day) should be administered from days 16 to 26 to \navoid endometrial hyperplasia (Fish 2011; Cartwright et al. \n2016). Estrogen-progestin HRT elevates breast cancer risk \nby approximately 1.3 times after more than 5 years (Cart -\nwright et al. 2016; Kou et al. 2016).\nGonadotropin‑releasing hormone agonists\nGonadotropin-releasing hormone (GnRH) analogs, particu-\nlarly agonists, are extensively researched for their ability \nto protect ovarian function during gonadotoxic therapies, \nsuch as chemotherapy, which may result in POF. Their main \nobjective is to avert or diminish ovarian damage, hence sav-\ning future reproductive potential (Blumenfeld 2019a; Blu-\nmenfeld and Wolff 2008). GnRH agonists are not recognized \nas a main method for fertility preservation in spontaneous \nPOF due to the lack of functioning follicles. Their role con-\nnects with POF settings. GnRH agonists, such as leuprolide, \ninitially induce a “flare effect,” subsequently leading to pitui-\ntary desensitization and suppression of FSH and LH. This \ndiminishes ovarian activity, apparently saving follicles from \nharm during chemotherapy. GnRH agonists may protect fol-\nlicles from apoptosis following cytotoxic therapy by induc-\ning a brief prepubertal hormonal state. Reducing ovarian \nperfusion, therefore, restricts chemotherapeutic exposure to \nthe ovary, mitigating apoptosis in ovarian cells via the acti-\nvation of intra-ovarian protective factors (Yuan et al. 2022). \nGnRH agonists are not used as treatment for confirmed POF. \nTheir function is prophylactic, so they should be provided \nbefore and during cytotoxic therapy to mitigate the chance \nof developing POF. Clinical trials and meta-analyses indi -\ncated that concurrent administration of GnRH agonists dur-\ning chemotherapy markedly reduced the incidence of POF \nand enhanced the likelihood of restarting menstruation and \novarian function following treatment (Blumenfeld and Wolff \n2008; Blumenfeld et al. 2014; Blumenfeld 2019b).\nOocyte cryopreservation\nOocyte cryopreservation, sometimes referred to as egg freez-\ning, is a medical process that involves the collection, fast \nfreezing, and storage of a woman’s eggs (oocytes) for future \nutilization. This procedure is a crucial technique employed \nto maintain fertility (Han and Seifer  2023). Oocyte cryo -\npreservation is a recognized method for maintaining fertility \nin women susceptible to POF. This method is particularly \ncrucial for women undergoing gonadotoxic medications, \npossessing genetic predispositions, or experiencing medi -\ncal disorders that may diminish ovarian reserve (Pai et al. \n2021). Oocyte cryopreservation is useful for early-stage \nPOF in women with irregular ovulation and a detectable \nantral follicle count or anti-Müllerian hormone (AMH), par-\nticularly those with hereditary predispositions (Oktay and \nBedoschi 2014), autoimmune, or iatrogenic POF (González \net al. 2012; Tomasi-Cont et al. 2014). The procedure of \noocyte cryopreservation transpires through multiple stages. \nIn initial ovarian stimulation, the female receives hormo -\nnal treatment to produce numerous mature oocytes. Subse -\nquently, egg retrieval occurs, during which mature oocytes \nare extracted from the ovaries via a small surgical inter -\nvention. After cryopreservation, the harvested oocytes are \noften frozen using a method known as vitrification, which \ninhibits ice crystallization within the cells. Ultimately, the \nfrozen eggs are preserved in liquid nitrogen until the mother \ndecides to utilize them. In the future, when pregnancy is \nrequested, the ova are thawed, fertilized with sperm in vitro, \nand subsequently implanted as embryos into the uterus (Han \nand Seifer 2023; Han and Seifer 2023).\nMolecular mechanisms promoting \ncyclophosphamide‑induced ovarian injury\nCP induces ovarian damage primarily through oxidative \nstress, inflammation, and apoptosis. Its bioactivation leads to \nexcessive generation of ROS, including superoxide (O ₂•⁻), \nhydrogen peroxide (H ₂O₂), singlet oxygen, and hydroxyl \nradicals (•OH), disrupting redox homeostasis in ovarian \ntissue (Trujillo et al. 2023). CP also elevates nitric oxide \n(NO) levels, which rapidly react with superoxide to form \nperoxynitrite (ONOO⁻), a highly reactive oxidant that inten-\nsifies cellular injury (Khan et al. 2016; Shaeib et al. 2016). \nThis oxidative burden impairs mitochondrial function and \ndepletes antioxidant defenses, creating a self-propagating \ncycle of damage (Oyagbemi et al. 2016; Chen et al. 2007). \nConsequently, mitochondrial dysfunction activates intrinsic \n1956 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\napoptotic signaling through cytochrome c release and cas -\npase-3 activation, contributing to granulosa cell (GC) death \nand follicular depletion (Goud et al.  2014; Liu et al. 2016).\nInvolvement of oxidative stress \nin cyclophosphamide‑induced ovarian injury\nOxidative stress is a pathological condition characterized \nby an imbalance between the production of ROS and the \nability of the body’s antioxidant defense system to neutral-\nize these harmful species. This disruption in redox homeo -\nstasis results in cellular damage, including lipid peroxida -\ntion, DNA damage, and inflammation (Ali et al. 2024). CP \ninduces oxidative stress in the ovary by generating ROS \nand impairing the antioxidant defense mechanism. Elevated \nlevels of malondialdehyde (MDA), a marker of lipid peroxi-\ndation, have been observed following CP exposure (Chen \net al. 2024a). CP also suppresses key antioxidant enzymes \nsuch as catalase, superoxide dismutase (SOD), and glu -\ntathione (GSH), thereby exacerbating ROS accumulation \nand mitochondrial dysfunction (Doğan et al. 2015; Nafees \net al. 2015). Additionally, downregulation of the Nrf2 sign-\naling pathway further impairs redox homeostasis (Ngo and \nDuennwald 2022). Collectively, these changes contribute to \noxidative DNA damage, lipid peroxidation, and follicular \napoptosis (Trujillo et al. 2023; Barberino et al. 2023). In the \ncontext of breast cancer, both ellagic acid and curcumin, \nnatural polyphenolic compounds, have been highlighted for \ntheir role in regulating oxidative stress to restore cellular \nequilibrium and protect against oxidative-stress-induced cell \ninjury (Golmohammadi et al. 2023; Golmohammadi et al. \n(2024).\nInvolvement of inflammation \nin cyclophosphamide‑induced ovarian injury\nCP promotes ovarian inflammation by upregulating key \ninflammatory mediators, including NF-κB, tumor necrosis \nfactor alpha (TNF-α), interleukin-1 beta (IL-1β), interleu -\nkin-6 (IL-6), and cyclooxygenase-2 (COX-2), all of which \nare closely linked to ovarian dysfunction (Gupta et al. \n2010). Ovarian injury caused by CP leads to the release of \ndamage-associated molecular patterns (DAMPs), which \nactivate pattern recognition receptors (PRRs) such as Toll-\nlike receptors, NOD-like receptors, and others on immune \nand non-immune cells (Ma et al. 2024). Activation of \nTLR4 triggers the NF-κB signaling pathway, resulting in \nincreased expression of proinflammatory cytokines like IL-6 \nand TNF-α (Ding et al. 2016; Makled et al. 2016). While \nDAMP–PRR interactions serve a protective function, their \nexcessive activation in response to CP exacerbates inflam -\nmation and contributes to ovarian damage (Ma et al. 2024).\nInvolvement of apoptosis \nin cyclophosphamide‑induced ovarian injury\nApoptosis is a key mechanism underlying CP-induced ovar-\nian follicle depletion and contributes significantly to POF \n(Hassan et al. 2014; Xie et al. 2024). CP triggers both the \nintrinsic (mitochondrial) and extrinsic (death receptor-medi-\nated) apoptotic pathways, primarily through oxidative stress \nand inflammatory signaling (Elmore 2007). The toxic CP \nmetabolite acrolein promotes excessive ROS production, \nwhich damages mitochondrial membranes, induces lipid \nperoxidation, and impairs DNA integrity. This activates the \nintrinsic pathway via mitochondrial outer membrane perme-\nabilization, releasing cytochrome C and forming the apopto-\nsome complex with apoptotic protease activating factor-1 \n(Apaf-1) and procaspase-9 (Hashemi et al.  2004; Ghavami \net al. 2004). Caspase-9 then activates caspase-3, leading to \nDNA fragmentation and cell death. These effects are accom-\npanied by increased expression of pro-apoptotic proteins \nBcl-2-associated X protein (Bax), p53, and decreased levels \nof anti-apoptotic B-cell lymphoma 2 protein (Bcl-2) (Los \net al.  1995; Ghobrial et al. 2005; Yuan and Akey 2013; Jin \nand El-Deiry 2005). In parallel, CP-induced cytokines such \nas TNF-α and Fas ligand engage their receptors, forming \nthe death-inducing signaling complex (DISC) and activat -\ning caspase-8 (Jin and El-Deiry 2005; Guicciardi and Gores \n2009). This initiates the extrinsic pathway and further ampli-\nfies mitochondrial damage through BH3 interacting domain \ndeath agonist (BID) cleavage, linking both pathways at the \nmitochondrial level (Stergiou and Hengartner 2004). CP-\nevoked apoptosis via both intrinsic and extrinsic pathways \nis illustrated in Fig.  2.\nInvolvement of TLR4 and NF‑κB signaling pathway \nin cyclophosphamide‑induced ovarian injury\nIt is generally agreed that TLRs, which belong to the cat -\negory of transmembrane pattern recognition receptors, are \nessential components of the innate immune system. The \nmajority of their expression can be found on a variety of \ninnate immune cells, including mast cells, macrophages, and \ndendritic cells of the immune system (Nardo 2015; Kawa-\nsaki and Kawai 2014). According to the findings of several \nstudies, the activation of TLRs has a significant impact on \nneuroinflammation and behavioral abnormalities that are \nbrought on by chemotherapeutic medicine (Squillace and \nSalvemini 2022; Vichaya et al. 2015). There is a correlation \nbetween TLR4 activation and CP-induced neurotoxicity, as \nwell as the following surplus output of pro-inflammatory \ncytokines and their important role in the pathophysiology of \nthe cognitive impairment that is associated with this condi -\ntion, according to a study that was conducted not too long \n1957Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nago (Ren et al. 2019). TLR signal transduction transpires \nthrough two primary channels: the myeloid differentiation \nprimary response 88 (MYD-88)-independent and MYD-\n88-dependent pathways, which engage a consortium of \nadaptor proteins that facilitate the propagation of activation \nsignals and amplify pro-inflammatory responses (Ashay -\neri Ahmadabad et al. 2021). TLR connects with MyD88 \nat the toll-interleukin 1 receptor (TIR) domain-containing \nadaptor protein (TIRAP), which is one of the steps in the \nMyD88-dependent pathway that leads to the recruitment of \nIL-1 receptor-associated kinase (IRAK) (Deguine and Bar -\nton  2014). In response to its activation, IRAK is responsible \nfor activating TNF receptor-associated factor 6 (TRAF6). At \nsome point in time, these signaling cascades will eventually \nphosphorylate and promote the IKK complex. This complex \nwill then phosphorylate IκB, making it susceptible to deg -\nradation by proteasomes, resulting in nuclear translocation \nof NF-κB, which in turn initiates the transcription of many \ngenes that promote inflammation. Additionally, TRAF6 can \nactivate mitogen-activated protein kinases of the MaPK \nfamily. MaPKs are responsible for activating several tran -\nscription factors, one of which is activator protein 1 (AP-1), \nwhich in turn causes the synthesis of a great deal of inflam-\nmatory mediators (Kawasaki and Kawai 2014; Hou et al. \n2017; Walsh et al. 2015). On the other hand, in the path -\nway that is not dependent on MyD88, TLR is responsible \nfor recruiting adaptor proteins such as translocating chain-\nassociated membrane protein (TRAM) and TIR-domain-\ncontaining adaptor-inducing interferon (TRIF). Interferon \nregulatory factor 3, also known as IRF3, is activated when \nthese two proteins go through the process of dimerization, \nwhich ultimately results in the release and production of \ninterferon beta, also known as IFN-γ (Duan et al. 2022; \nUllah et al. 2016). NF-κB is the primary transcription fac -\ntor that is responsible for regulating the synthesis of several \ngenes that are associated with inflammation. Several studies \nhave demonstrated that the occurrence of CP-induced ovar-\nian injury is closely associated with the intensification of \ninflammatory responses. This intensification is facilitated \nby the upregulation of TLR4/NF-κB expression, which in \nturn leads to the overproduction of inflammatory mediators. \nThese mediators include TNFα, nitric oxide (NO), IL-1β, \nand IL-6 (Khallaf et al. 2023; Ran 2015). The activation of \nthe pathway is illustrated in Fig.  3.\nFig. 2  Extrinsic and intrinsic pathways of apoptosis. This figure illus-\ntrates the two main pathways of apoptosis. The extrinsic pathway \n(left) is initiated by death ligands binding to death receptors, leading \nto the formation of DISC and subsequent caspase-3 activation. The \nintrinsic pathway (right) involves mitochondrial dysfunction triggered \nby cellular stress, resulting in cytochrome c release, apoptosome for -\nmation, and caspase-3 cascade activation\n1958 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nRole of NLRP3 inflammasome/caspase 1 signaling \npathway in cyclophosphamide‑induced ovarian \ninjury\nInflammasomes, which are multiprotein complexes, assemble \nin the cytoplasm and are triggered by many endogenous and \nexogenous stimuli, including ROS and DAMPs. It has been \nestablished that inflammasomes comprise many subtypes \n(Blevins et al. 2022a; Dai et al. 2020). The most prominent \namong them is the NLRP3 inflammasome. Upon stimulation, \nprocaspase 1, NLRP3, and apoptosis-associated speck-like \nprotein (ASC) converge to form the NLRP3 inflammasome \n(Zheng et al. 2020a; Blevins et al. 2022b). In subsequent \nsteps, the activation of pro-caspase 1 results in the formation \nof active caspase 1, which in turn degrades pro-IL-1β and \npro-IL-18 into their mature and dynamic forms. This causes \nan increase in the production of additional inflammatory \ncytokines, which in turn causes the inflammatory responses \nto become more intense (Kelley et al. 2019; Abdelnaser et al. \n2025a). It has been found that ovarian failure is related to an \naggressive inflammatory response. Pyroptosis is characterized \nby the production of proinflammatory intracellular agents, \nsuch as IL-18 and IL-1β, in addition to the creation of pores \nin the plasma membrane, cellular swelling, and membrane \nrupture that are induced by the gasdermin family. Gasdermin \nD (GSDMD) is cleaved by activated caspase-1, which results \nin the formation of membrane holes that promote pyroptosis \n(Liu et al. 2018a; Shi et al. 2015). The transcription factor \nthat ultimately increases the synthesis of proinflammatory pro-\nteins, including pro-IL-1β, pro-IL-18, NLRP3, and caspase-1, \nis mostly governed by NF-κB, which provides a significant \namount of overall control (Shi et al. 2015; Du et al. 2020). CP-\ninduced ovarian damage is highly connected with this pathway, \nas revealed by several investigations (Zhang et al. 2021; Vin-\ndevogel et al. 2016; Navarro-Pando et al. 2021). The assembly \nof the NLRP3 inflammasome is shown in Fig. 4.\nRole of SIRT1 in cyclophosphamide‑induced ovarian \ninjury\nSIRT1 plays a significant part in preserving the function of \novarian tissue and reducing the negative effects of ovarian \naging (Li et al. 2023b). Several investigations have estab -\nlished SIRT1’s regulatory role within the granulosa cells \n(Rofaeil et al. 2024). Zhao and colleagues subsequently \nidentified that SIRT1 is involved in regulating processes \nassociated with follicular atresia through GC apoptosis in \nporcine ovaries exhibiting follicular atresia (Zhao et al. \n2014). Through the activation of SIRT1, Nie et al. were able \nto successfully ameliorate the effects of CP-induced POF in \nFig. 3  The assembly and activation of the TLR4 pathway. This figure \ndepicts the innate immune response to DAMPs released from injured \ncells due to cyclophosphamide. DAMPs are recognized by TLRs on \nmacrophages, dendritic cells, and mast cells. TLR activation triggers \ndownstream signaling cascades involving adaptor proteins (MyD88, \nTIRAP, TRAM, TRIF) and kinases (IRAK), leading to activation of \nTRAF-6 and IRF3. These transcription factors, along with NF-κB, \nAP-1, and interferon regulatory factors, translocate to the nucleus to \ninduce expression of inflammatory cytokines\n1959Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\na mouse ovarian model. This was accomplished by signifi -\ncantly lowering the expression of the pro-apoptotic protein \nBax and increasing the production of the anti-apoptotic pro-\ntein Bcl-2 (Wang and Li 2021). Han et al. found that SIRT1 \nimproved the resilience of granulosa cells to apoptosis (Han \net al. 2017). Similar findings were discovered by Sirotkin \nin swine ovarian granulosa cells. In these cells, SIRT1 has \nbeen demonstrated to influence the transcription factors p53 \nand NF-κB, both of which are involved in the modulation of \nGC apoptosis and proliferation (Sirotkin et al. 2014). The \nsynthesis of the SIRT1 enzyme in ovarian cells is markedly \ndiminished in CP-induced ovarian damage, which exacer -\nbates inflammatory responses (Li et al. 2023b; Chen et al. \n2024b). The mechanism by which SIRT1 hinders the activity \nof several redox-sensitive pro-inflammatory mediators, such \nas NF-kB and NLRP3, can shed light on this phenomenon. \nSIRT1 can restrict the transcriptional activity of NF-κB \nthrough the process of deacetylation of the p65 subunit. This \nmay make it easier for the NF-kB complex to interact with \nIκB, which will then cause the NF-kB complex to move \nfrom the nucleus to the cytoplasm, reducing the expression \nof genes that are associated with inflammation (Gregorio \net al. 2020).\nRole of Nrf2/Keap1 pathway \nin cyclophosphamide‑induced ovarian injury\nNrf2 is the primary regulator of cellular responses to \nexternal stimuli (Kobayashi et al. 2004). Both antioxidants \nand detoxifying enzymes are encoded by the Nrf2, which \nmakes it possible for a redox-sensing system to function \n(Alaaeldin et al. 2024; Mohyeldin et al. 2025a). By causing \nits activity to be adversely modulated by proteasomal deg -\nradation, Kelch-like ECH-associated protein 1 (KEAP1) \nacts as a natural inhibitor of the natural regulatory factor \nNrf2 (Wang et al. 2008). In response to the presence of \nFig. 4  The assembly of the NLRP3/caspase-1/GSDMD pathway. This \nfigure illustrates the NLRP3 inflammasome activation pathway trig -\ngered by cyclophosphamide. DAMPs activate the NLRP3 inflamma -\nsome complex. The inactive NLRP3 protein oligomerizes to form the \ninflammasome that recruits the ASC and procaspase-1. This assembly \nleads to caspase-1 activation, which cleaves the inactive precursors \npro-IL-1β and pro-IL-18 into their mature forms\n1960 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nxenobiotics, the Nrf2/Keap1 pathway is activated, which \nleads to the release of Nrf2, which is accomplished by \ntranslocating to the nucleus. After that, it can affix itself \nto the sequences of the antioxidant response element, \nwhich are responsible for regulating several particular \ngenes, such as glutathione S-transferase and HO-1 (Tagu -\nchi et al. 2011). Nrf2 is a transcription factor that targets \ngenes that encode enzymes involved in the metabolism \nof drugs, transporters, antioxidant enzymes, and enzymes \ninvolved in the metabolism of heme and iron. Through \nthe reduction of cell death and the enhancement of the \ncellular redox state, hyperactivation of Nrf2 was able to \nminimize oxidative stress (Suzuki et al. 2013; Mohyeldin \net al. 2025b). Several studies conducted in the past have \nshown that ovarian damage caused by CP is associated \nwith a decrease in the expression of Nrf2 (Li et al. 2024; \nEl-Marasy et al. 2025; Chen et al. 2021).\nRole of α‑klotho in cyclophosphamide‑induced \novarian injury\nThose individuals who have been diagnosed with POF have \na notable decrease in the expression of α-Klotho, which \nsuggests a solid connection between decreased levels of \nα-Klotho and the onset of ovarian aging (Xie et al. 2021). \nKlotho expression was dramatically reduced in animal mod-\nels of CP-induced POF compared to the control group (Liu \net al. 2019a). Prior research revealed that rats intoxicated \nwith CP had a marked decrease in ovarian α-Klotho, while \nthe elevation of α-Klotho levels alleviated the ovarian dam-\nage induced by CP (Biyik et al. 2021; Khallaf et al. 2025; \nRofaeil et al. 2025). The pathological function of α-Klotho \nin POF remains inadequately elucidated; nevertheless, it \ncan be interpreted by viewing POF as a pathological aging \nphenomenon, given the depletion of ovarian reserve dur -\ning POF. An earlier study has shown that α-Klotho plays \na significant role in the development of oocytes by aiding \nmaturation through the activation of wingless-related inte -\ngration site (Wnt) signaling pathways (Kim et al. 2020, \n2023) as well as controlling the development of ovarian \nfolliculogenesis through the phosphoinositide 3-kinase \n(PI3K)/protein kinase B (AKT)/mammalian target of rapa -\nmycin (mTOR) pathway (Hu et al. 2022). The decrease in \novarian α-Klotho expression led to a decrease in autophagy, \nwhich negatively impacted the cells’ ability to eliminate \nROS. This, in turn, disrupted the normal cellular activity \nand triggered apoptosis, which ultimately led to a loss of \novarian reserve (Liu et al. 2019b; Sachs-Guedj et al. 2024). \nFurthermore, recent research has provided evidence to sup-\nport the idea that the activation of α-Klotho inhibited the \nTLR4 signaling pathway (Typiak and Piwkowska 2021), \napoptosis (Sugiura et al. 2005), and oxidative stress (Oh \net al. 2015; Abdelnaser et al. 2025b).\nRole of the PTEN\\PI3K\\AKT pathway \nin cyclophosphamide‑induced ovarian injury\nIn both healthy and pathological conditions, the PI3K/AKT/\nmTOR signaling pathways are crucial for several aspects \nof cellular development and survival (Porta et al. 2014). \nPI3K is responsible for facilitating the phosphorylation \nof phosphatidylinositol, which in turn regulates processes \nsuch as cell motility, survival, differentiation, growth, and \nintracellular transport (Cully et al. 2006). The term “protein \nkinase B” (PKB) or “AKT” refers to a group of three serine/\nthreonine-specific protein kinases that may be involved in a \nvariety of cellular processes, such as apoptosis, proliferation, \ntranscription, and migration (Revathidevi and Munirajan \n2019; Mohyeldin et al. 2024). The PI3K/AKT pathway gen-\nerates intracellular signaling cascades and comprises many \nsignaling molecules, including kinases, phosphatases, and \ntranscription factors. This prominent intracellular signaling \npathway also contributes to the stimulation of primordial fol-\nlicles in the ovary (Cantley 2002). The AKT kinase, which \nplays a significant role in the activation of primordial fol -\nlicles, exerts both direct and indirect effects on the activa -\ntion of follicles through a wide variety of substrates that \nare present in human ovarian granulosa cells and oocytes \n(Cecconi et al. 2012). Among the many AKT substrates, the \nforkhead box O3 (Foxo3) protein was initially recognized \nas a regulator of the primordial follicle activation pathway. \nThis discovery was made available to researchers. Experi -\nments have shown that the expression of the active Foxo3 \ngene in mouse oocytes causes a delay in the development of \noocytes and follicles. This is because all dormant follicles \nin the pubertal ovary are triggered prematurely in animals \nthat are lacking in the Foxo3 gene. This suggests that the \nnormal expression of the Foxo3 gene can prevent the for -\nmation of follicles and keep follicles in a dormant condition \n(Liu et al. 2007). An investigation conducted by Goldbraikh \nand colleagues revealed that the PI3K/AKT/Foxo3 signaling \npathway is the primary mechanism responsible for control -\nling growth and metabolism in every cell (Goldbraikh et al. \n2020). The action of the phosphatase and tensin homolog \ngene PTEN, which inhibits the PI3K/AKT pathway, causes \nprimordial follicles to remain dormant for a significant \nperiod throughout the process of follicle development. \nAfter PTEN inhibition has been removed from primordial \nfollicles, PI3K activation takes place in these cells. This \nultimately resulted in the transition of phosphatidylinositol \n4,5-bisphosphate into phosphatidylinositol-3, 4, 5-triphos -\nphate, which in turn activated phosphoinositide dependent \nprotein kinase-1 and stimulated AKT. Primordial follicles \nare activated when the Foxo3 protein, which is located far \ndownstream, is phosphorylated. This causes the Foxo3 pro-\ntein to lose its ability to perform transcriptional functions \nand causes it to move from the nucleus to the cytoplasm, \n1961Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nwhere it is then targeted for degradation (John et al. 2008). \nAs a result of its role as a negative regulator of PI3K, PTEN \ncan block the PI3K signaling pathway. It has been demon -\nstrated through research that the activation of latent primor-\ndial follicles occurs when the expression of the PTEN gene \nis suppressed in mice because of increased activity in the \nPI3K signaling pathway. By removing the PTEN gene from \nthe oocytes of mouse primordial follicles, it is possible that \nthe formation of primordial follicles and the early activation \nof the entire primordial follicle pool during puberty would \nbe facilitated. Not only does this cause follicular depletion \nin early adulthood mice, but it also occurs in POF in mice \n(Adhikari et al. 2012). Animal studies indicate that the \nPTEN/PI3K/AKT signaling pathway is mostly responsible \nfor maintaining follicular dormancy or facilitating follicle \nactivation (2010). The ovarian follicular reserve is swiftly \ndiminished and prematurely activated in genetically modi -\nfied mouse models when one or more components of this \npathway are deliberately eliminated in the oocyte (Castrillon \net al. 2003). Short-term activation of PI3K or suppression of \nPTEN in human cortical tissue facilitates follicle develop -\nment and results in the depletion of primordial follicles (Li \net al. 2010). CP influences the PI3K/AKT pathway in two \ndistinct ways. Overactivation of PI3K/AKT induces prema-\nture activation of the dormant follicle pool and follicular \nburnout, culminating in fast depletion and eventual POF, \nwhereas inhibition of PI3K/AKT may transpire in devel -\noping follicles, resulting in GC death and follicular atresia \n(Zhang et al.  2018; Zhou et al. 2017).\nInterconnected molecular pathways underlying \ncyclophosphamide‑induced ovarian injury\nCP-induced POF involves a highly interconnected molec -\nular cascade, where oxidative stress acts as the central \ninitiator. The metabolic byproducts of CP, particularly \nacrolein, generate excessive ROS, disrupting redox bal -\nance and damaging ovarian cellular components (Nie \net al. 2021). This oxidative burden serves as a trigger for \ninnate immune signaling, particularly through the activa -\ntion of TLR4, which subsequently activates the NF-κB \npathway. NF-κB translocates to the nucleus and drives the \nexpression of pro-inflammatory cytokines such as TNF-α, \nIL-1β, and IL-6, which not only propagate inflammation \nbut also contribute to the activation of the NLRP3 inflam -\nmasome (Zhang et al. 2021). The NLRP3 complex pro -\nmotes the cleavage of pro-caspase-1 into active caspase-1, \nfacilitating the maturation and release of IL-1β and IL-18, \namplifying inflammation and pyroptosis within the ovar -\nian microenvironment (Yin et al. 2023). Parallel to this, \nsustained oxidative and inflammatory stress destabilizes \nmitochondrial integrity, activating the intrinsic apoptotic \npathway. This leads to the release of cytochrome c and \nsubsequent activation of caspase-9 and executioner cas -\npase-3, resulting in GC apoptosis and follicular depletion. \nUnder physiological conditions, the Nrf2 pathway acts as \na primary defense mechanism by inducing antioxidant \nenzymes such as HO-1, SOD, and catalase. However, CP \nsuppresses Nrf2 signaling, weakening the cellular defense \nmechanism. SIRT1, a redox-sensitive NAD ⁺-dependent \ndeacetylase, normally exerts cytoprotective effects by \ninhibiting NF-κB, promoting Nrf2 activation and main -\ntaining mitochondrial function; its downregulation under \nthe effect of CP further impairs these protective responses \n(El-Marasy et al. 2025). Additionally, α-Klotho, an anti-\naging protein with known antioxidant and anti-apoptotic \nfunctions, is reduced by CP exposure. This reduction \ncontributes to heightened oxidative damage, inflamma -\ntion, and apoptotic sensitivity. α-Klotho also positively \ninfluences SIRT1 and Nrf2 signaling, suggesting a feed -\nback loop wherein its depletion accelerates ovarian injury \n(Rofaeil et al. 2025). Altogether, these pathways form a \ntightly integrated network, where oxidative stress, inflam -\nmatory signaling, and apoptosis reinforce one another, \nwhile regulatory pathways such as Nrf2/HO-1, SIRT1, \nand α-Klotho are suppressed, shifting the cellular balance \ntoward damage and follicular loss.\nTherapeutic protection \nagainst cyclophosphamide‑induced ovarian \ninjury in experimental studies\nBuspirone\nBuspirone (BUS) is a medication frequently prescribed \nfor anxiety and depression, Functioning as a partial ago -\nnist at 5-HT ₁A receptors and an antagonist at dopamine \nD₂ receptors through presynaptic modulation of seroto -\nnin release (Loane and Politis 2012; Abdel-Salam et al. \n2017 ). It has also been used adjunctively to manage \nchemotherapy-induced dyspnea and emesis in patients \ntreated with CP (Alfieri and Cubeddu 1995 ; Wolff and \nLeander 1997; Peoples et al. 2016). Additionally, BUS \nimproved gastric accommodation and relieved gastropare -\nsis conditions, often associated with chemotherapy-related \nneuropathy or tumor burden (Parkman et al. 2023; Sayuk \n2023). Beyond its gastrointestinal effects, BUS has shown \npotential in mitigating vasomotor and sexual symptoms \nsuch as hot flashes and hypoactive sexual desire, which \nare commonly observed in women with POF (Shumilov \nand Touitou 2010; Croft 2017). Recent studies demon -\nstrated that BUS exerts anti-inflammatory and antioxidant \nactions via multiple pathways. It downregulates NLRP3 \ninflammasome activity, suppresses the TLR4/NF-κB axis, \n1962 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nand activates the Nrf2/HO-1 signaling cascade, offering \nneuroprotection and reducing inflammation in various \nanimal models (Althagafy et al. 2023 ; Rashidian et al. \n2022). BUS also modulates apoptosis by influencing the \nBax/Bcl-2/caspase-3 pathway (Sharifi et al. 2015 ) and \nsupports metabolic regulation via AMP-activated protein \nkinase (AMPK) pathway activation (Lee et al. 2023). In \nCP-induced POF, BUS has been shown to mitigate oxi -\ndative stress, inflammation, and apoptosis. These effects \nare mediated through inhibition of the NF-κB/NLRP3/\ncaspase-1 and Bax/Bcl-2/caspase-3 pathways, alongside \nactivation of Nrf2/HO-1, p-AMPK, and α-Klotho signal -\ning (Khallaf et al. 2025). Its established side effects in the \nclinical setting include dizziness, headache, restlessness, \nnausea, and, less commonly, serotonin syndrome when \ncombined with other serotonergic drugs (Loane and Politis \n2012). Importantly, there is a lack of direct clinical data \nregarding long-term reproductive safety in humans.\nLevomilnacipran\nLevomilnacipran (LVM) is a selective serotonin and nor -\nepinephrine reuptake inhibitor (SNRI) approved by the \nFDA in 2013 for the treatment of major depressive disorder \n(Fanelli et al. 2021; Sharata et al. 2025). To enhance func-\ntional recovery in individuals who have suffered an ischemic \nstroke, LVM is currently undergoing development and has \nadvanced to a phase II clinical trial (Hair et al. 2013a). It \nexhibits analgesic effectiveness and mitigates weariness \nlinked to depression (Hair et al. 2013a, 2013b). Its favora-\nble safety profile and low discontinuation rate contribute \nto strong patient adherence (Asnis and Henderson 2015; \nMontgomery et al. 2013). LVM is also used to treat fibro -\nmyalgia, neuropathic pain, and burning mouth syndrome, \nwhich commonly affect female cancer patients undergoing \nchemotherapy (Deardorff and Grossberg 2014; Saraceni \net al. 2014; Bernstein et al. 2013; Ohnami et al. 2012). Addi-\ntionally, women with cancer or fibromyalgia often experi -\nence comorbid depression and hot flashes, symptoms for \nwhich SNRIs have demonstrated benefit (Thiagarajah et al. \n2014; Yepez et al.  2022; Raison and Miller 2003). Recent \nevidence showed that LVM exerts neuroprotective and anti-\ninflammatory effects by suppressing the TLR4/p38 MAPK/\nNF-κB and Bax/Bcl-2/caspase-3 pathways (Wu et al. 2024; \nLi et al. 2023c). In a rat model of CP-induced POF, LVM \nsignificantly reduced ovarian oxidative damage, inflamma -\ntion, and apoptosis via suppression of the TLR4/p38 MAPK/\nNF-κB and Bax/Bcl-2/caspase-3 pathways, in addition to the \nactivation of the α-Klotho protein pathway (Rofaeil et al. \n2025). It is primarily associated with side effects such as \nnausea, increased heart rate, hyperhidrosis, constipation, uri-\nnary hesitation, sexual dysfunction, and potential increases \nin blood pressure (Asnis and Henderson 2015).\nCilostazol\nCilostazol is a derivative of the 2-oxo-quinoline system \nthat possesses antithrombotic, vasodilatory, antimitogenic, \nand cardiotonic properties. This compound is an extremely \neffective inhibitor of phosphodiesterase-3A (Abdel-Aziz \net al. 2020). Cilostazol has been shown to have consider -\nable antithrombotic effects in vivo, as well as to inhibit the \naggregation of platelets (Minami et al.  1997). Cilostazol can \neffectively lower serum triglyceride levels while simultane-\nously causing a little elevation in HDL cholesterol levels \n(Elam et al. 1998). Cilostazol significantly reduced ovarian \ntissue oxidative stress markers in rats treated with CP via \ndecreasing MDA levels and increasing SOD and GSH levels \ncompared to control rats (Abdel-Aziz et al. 2020). Cilosta-\nzol elevates intracellular cyclic nucleotides, and increased \namounts of these nucleotides have been demonstrated to \ndiminish ROS production and cellular dysfunction. In the \ncomparison between the treated group and the CP group, \na notable enhancement in the ovarian gene expression of \nHO-1 and Nrf2 was observed. Consequently, the antioxidant \nand anti-inflammatory effects of cilostazol in CP-associated \novarian toxicity are related to HO-1 induction (Abdel-Aziz \net al. 2020). Cilostazol inhibited ovarian apoptosis and alle-\nviated CP-induced ovarian destruction by upregulating HO-1 \nand cyclic adenosine monophosphate. It can cause headache, \npalpitations, diarrhea, dizziness, and edema. In patients with \nheart failure or arrhythmias, cilostazol is generally contrain-\ndicated due to the risk of increased cardiac events (Kherallah \net al. 2022).\nDiosmin\nDiosmin is a recognized natural flavonoid utilized in the \ntreatment of varicose veins and chronic venous insufficiency \n(Zheng et al. 2020b). Recent investigations have demon -\nstrated that diosmin possesses a broad spectrum of phar -\nmacological activities, including anti-inflammatory effects \n(Berköz  2019), antioxidant (Srinivasan and Pari 2012), anti-\ndiabetic (Hsu et al. 2017), anti-cancer (Naso et al. 2016), and \nretinal protection properties (Tong et al. 2013). An earlier \npreclinical study demonstrated the effectiveness of diosmin \nagainst CP-induced POF. The study included hormonal \nevaluations of FSH, estradiol (E2), and AMH, as well as \nhistopathological examinations of ovarian tissues, evalua -\ntions of oxidative stress levels, and measurements of the \nrelative expression of microRNA-145 in conjunction with its \ntarget genes, vascular endothelial growth factor B (VEGF-B) \nand regulator of cell cycle (RGC32). Oxidative stress indica-\ntors, as well as levels of AMH and E2, were all improved by \ndiosmin therapy. At both low and high dosages of diosmin, \nthe histological changes were greatly alleviated. The level \nof expression of miRNA-145 was shown to be enhanced \n1963Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nfollowing the administration of a high dose of diosmin. The \nadministration of diosmin resulted in a significant decrease \nin the number of atretic follicles and an increase in the total \ncount of developing follicles at various stages of folliculo -\ngenesis within the ovarian cortices. The results were depend-\nent on the dosage that was administered (Abogresha et al. \n2021). Being a natural flavonoid, diosmin’s side effects are \ngenerally mild, such as gastrointestinal upset, headache, or \nmild skin reactions. Allergic reactions are rare (Gerges et al. \n2022). Long-term reproductive safety data are scarce, as \nusage is mostly extrapolated from its vascular applications.\nDonepezil\nDonepezil is a selective acetylcholinesterase inhibitor com-\nmonly administered for individuals with mild to moderate \nAlzheimer’s disease (Rogers and Friedhoff 1996; Rogers \nS, Farlow M, Doody R, Mohs R, Friedhoff L, Group* DS \n1998; Burns et al. 1999). Donepezil has also demonstrated \nefficacy for persons at both extremes of the Alzheimer’s dis-\nease spectrum: benign, incipient conditions (Seltzer et al. \n2004) and those with moderate-to-severe impairment (Feld-\nman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen \nE, Group* DMSI 2001), including patients in nursing homes \n(Tariot et al. 2001). Moreover, cholinesterase inhibitors like \ndonepezil may prove beneficial in vascular dementia (Black \net al. 2003; Wilkinson D, Doody R, Helme R, Taubman K, \nMintzer J, Kertesz A, Pratt R, Group* DS 2003) and dementia \nassociated with Parkinson’s disease (Leroi et al. 2004; Aars-\nland et al. 2002). In the experimental model of CP-induced \nPOF, donepezil was found to increase serum AMH levels \nin a dose-dependent manner. A decrease in the expression \nof ovarian TLR4, NLRP3, IL-6, and TNF-α was observed \nwhen donepezil was administered. Furthermore, donepezil \nrestored all histopathological aberrations caused by CP. This \nwas demonstrated by the presence of typically growing fol-\nlicles in the early stages of maturation and a reduced number \nof atretic follicles. An increase in the dose of donepezil led \nto an improvement in the protection, as demonstrated by the \npresence of healthier follicles and a decrease in the number of \natretic follicles. The protective mechanism of donepezil was \nachieved by inhibiting the production of NO, proinflammatory \ncytokines, the TLR-4/NF-κB/NLRP3 inflammasome pathway, \nand apoptosis (Zidan et al. 2024). Donepezil causes gastro-\nintestinal disturbances (nausea, vomiting, diarrhea), muscle \ncramps, insomnia, bradycardia, syncope, and (rarely) cardiac \nconduction abnormalities, particularly in the elderly or those \nwith underlying heart disease (Jackson et al. 2004).\nLCZ696\nIn July 2015, the FDA authorized LCZ696, a pioneering \nmedicine that integrates sacubitril, a neprilysin enzyme \ninhibitor, and valsartan, an angiotensin II receptor AT1 \nantagonist, for the treatment of heart failure and perhaps \nhypertension (McMurray et al. 2014; Lm 2010; Hubers and \nBrown 2016). LCZ696 has shown the capacity to reduce \noxidative stress and inflammation by increasing endog -\nenous vasoactive peptide levels through neprilysin inhibi -\ntion (Mohyeldin et al. 2023). This is in addition to the ben -\nefits that it offers for the cardiovascular system (Jing et al. \n2017). LCZ696 improved endothelial function through the \ninhibition of the TLR4/NF-κB signaling pathway. LCZ696 \nwas able to reduce inflammatory responses, decrease the \nNLRP3 inflammasome, and offer protection against myo -\ncardial infarction and early diabetic nephropathy (Khallaf \net al. 2023; Shen et al. 2021; Li et al. 2020; Pan et al. 2022; \nGao et al. 2021). Through its antioxidant, anti-inflammatory, \nand anti-apoptotic activities, LCZ696 demonstrated a pro -\ntective effect against CP-induced ovarian damage in rats. \nThis protective effect can be interpreted based on two com-\nplementary suggested pathways, initially, through the direct \ninhibition of the NLRP3/caspase-1/GSDMD C-NT signal -\ning pathway. Furthermore, inhibiting the signaling path -\nway of TLR4, MYD88, and NF-B P65 ultimately resulted \nin a decrease in NLRP3, pro-IL-1β, pro-IL-18, and TNF-α \n(Khallaf et al. 2023). It is mainly associated with hypoten -\nsion, hyperkalemia, renal impairment, and, less commonly, \nangioedema. It is contraindicated in pregnancy due to tera -\ntogenic effects and potential fetal toxicity (Chua et al. 2021).\nMelatonin\nThe pineal gland is the principal producer of the indoleam -\nine hormone melatonin, which aids in the regulation of \nsleep–wake cycles and circadian rhythms (Stehle et al. \n1991). In addition to its chronobiological function, mela -\ntonin has several other beneficial impacts on different \norgans, such as the reproductive system, including reduc -\ning inflammation, preventing cell death, and protecting cells \nfrom free radicals (Reiter et al. 2016; Esposito et al. 2019; \nCipolla-Neto and Amaral (2018). Melatonin is produced in \nseveral organs, including the ovaries (Jang et al. 2017). It \ninfluences cellular signaling pathways that are involved in \ncell survival, oxidative stress response, and immunologi -\ncal regulation through melatonin receptors MT1 and MT2 \n(Jang et al. 2017). Melatonin has emerged as a promising \nfertoprotective agent against CP-induced ovarian injury, with \nevidence from animal studies and mechanistic investigations \n(Abdi et al. 2024). The melatonin administration before or \nalongside CP treatment preserved the ovarian reserve by \nmaintaining the number of primordial, primary, and growing \nfollicles, reducing follicular atresia, and activating the Hippo \nsignal pathway (Xu et al. 2022a). Melatonin helped to sus -\ntain physiological levels of AMH, E2, and inhibin B, while \nreducing elevated FSH and LH levels, thereby supporting \n1964 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\novarian endocrine function (Feng et al. 2022). It also inhib-\nited the apoptosis of granulosa cells, which are vital for fol-\nlicle survival and hormone production (Feng et al. 2022). \nMelatonin mitigated CP-induced oxidative stress and exces-\nsive autophagy in granulosa cells via modulating the PI3K/\nAKT/mTOR signaling pathway (Xu et al. 2022b; Barberino \net al. 2022; Liu et al. 2022). Melatonin is well-tolerated with \nminor side effects such as drowsiness, headache, and diz -\nziness. High doses may interfere with circadian rhythms, \naffect mood, or interact with anticoagulants (Anderson and \nMaes 2012).\nMoxibustion\nIn traditional Chinese medicine, moxibustion is the practice \nof lighting moxa at acupoints and in certain locations. Moxi-\nbustion protects against ulcerative colitis, post-inflammatory \nirritable bowel syndrome, and chronic exercise-induced \nfatigue (Li et al. 2019; Ma et al. 2016; Bao et al. 2019). Mox-\nibustion has been shown to reduce ovarian damage brought \non by CP by suppressing NLRP3 activation (Niu et al. 2022; \nZhao et al. 2010). The activation of NLRP3 inflammasome \nis mostly induced by excessive ROS produced from com -\npromised mitochondria. The age-related decrease in female \nfertility has been associated with the NLRP3 inflammasome, \nrendering this inflammatory complex a potential therapeutic \ntarget for infertility treatment. Inhibiting NLRP3 activation \ncan mitigate reproductive aging in female rats (Navarro-\nPando et al. 2021). Furthermore, it has been demonstrated \nthat animals that have NLRP3 inflammasome activation have \novarian dysfunction as well as fibrosis (Wang et al. 2020). \nThrough the reduction of mRNA and protein expression lev-\nels of NLRP3, ASC, GSDMD, and caspase 1, as well as the \nreduction of serum and ovarian levels of IL-18 and IL-1β, \nmoxibustion therapy, when administered to a rat model of \nCP-induced POF, demonstrated a significant suppression of \nNLRP3 activation (Yin et al. 2023). Moxibustion is consid-\nered very safe; risks include burns or allergic reactions, but \nsystemic adverse effects are rare and not observed in experi-\nmental ovarian injury models (Park et al. 2010).\nResveratrol\nSeveral plant species are used to extract resveratrol (RES), \na naturally occurring polyphenol compound (Oh and Sha -\nhidi 2018). RES is renowned for its cytoprotective effects \nagainst various diseases, attributable to its numerous bio -\nlogical activities, including anti-inflammatory, anti-cancer, \nanti-oxidative, anti-aging, and estrogen-regulatory proper -\nties (Athar et al. 2007). For in vitro-cultured follicles and \nzygotes, RES has a favorable regulatory effect (Sugiyama \net al. 2015). Furthermore, resveratrol is an SIRT1 activator \n(Howitz et al. 2003). A key player in controlling follicular \ngrowth and development is the SIRT1 signaling pathway \n(Zhou et al. 2015). Prior research has shown that rat granu-\nlosa cells express SIRT1 mRNA (Nie et al. 2020; Morita \net al. 2012). ROS buildup can be effectively removed by \nRES (Park and Pezzuto 2015). RES protects against ovarian \ninjury induced by chemotherapy by increasing the enzymatic \nactivity of SOD and CAT, and downregulating apoptosis. \nRES is a potent antioxidant that efficiently eliminates lipid \nperoxidation and DNA damage brought on by ROS (Leon -\nard et al. 2003). Under stressful circumstances, RES has \nbeen shown to affect cellular functions, including autophagy \nand the apoptotic cascade. The beneficial action of RES is \nlargely dependent on its concentration, and it shows strong \neffects in reducing ovarian injury (Nie et al. 2020). This \npolyphenol is generally well-tolerated, but high doses can \nlead to gastrointestinal upset, headache, or elevated liver \nenzymes in rare cases (Shaito et al. 2020).\nIrbesartan\nIrbesartan (IRB) is a synthetic non-peptide antagonist of \nangiotensin II that possesses agonistic activity for the per -\noxisome proliferator-activated receptor-gamma (PPAR- ɣ) \n(Vignier et al. 2014; Zhang et al. 2013). As PPAR-ɣ activa-\ntion produces anti-inflammatory effects and an improvement \nin endothelial function, lipid metabolism, and a reduction in \nROS production (Martin et al. 2012; Hu et al. 2014; Ibrahim \net al.  2025), IRB reduced inflammatory parameters and pre-\nvented apoptotic cell death (Anjaneyulu and Chopra 2004). \nSince PPAR-ɣ agonistic drugs such as IRB are responsible \nfor strong organ-protective effects, including anti-fibrotic, \nanti-oxidant, and anti-inflammatory effects, IRB was proven \nto be effective in protection from CP-induced ovarian injury \n(Wang et al. 2013a). As mentioned in the previous experi -\nmental study, serum FSH was increased, and serum estra -\ndiol was decreased after CP administration. Moreover, CP \nadministration significantly increased ovarian TNF-α, MDA, \nmyeloperoxidase (MPO), and caspase-3 levels. All previ -\nously mentioned parameters have been normalized after IRB \nadministration. On the other hand, IL-10, GSH levels, and \nSOD activity significantly decreased after CP administra -\ntion, which was corrected after IRB administration (Abdel-\nRaheem et al. 2015). The most typical side effects are hypo-\ntension, dizziness, hyperkalemia, and rare angioedema. Like \nall drugs in this class, they are contraindicated in pregnancy \ndue to established teratogenic risks (Bramlage et al. 2009).\nMirtazapine\nMirtazapine, often known as MTZ, is a medication that is \napproved for the treatment of serious depression (Davis \nand Wilde 1996). It also has antioxidant activity besides its \nantidepressant effect (Altuner et al. 2013). Previous studies \n1965Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nhave also stated that MTZ with various doses (15, 30, and \n60 mg/kg) significantly alleviated indomethacin-induced \nmucosal damage (El-Awdan and Zaki 2013). Given the \nanticipated prevalence of depression and anxiety among \ncancer patients due to the detrimental effects of chemo -\ntherapy and the heightened severity observed in infertile \nwomen, MTZ pretreatment in cancer patients undergoing \nCP as an anti-cancer therapy would be beneficial in vari -\nous respects (Altuner et al. 2013). A prior study indicated \nthat pretreatment with MTZ significantly enhanced ovarian \nweight and the number of mature follicles, which markedly \ndiminished following CP (Khedr 2015). In addition, the \nadministration of MTZ decreased the raised levels of NO \nand MDA, enhanced the activity of glutathione peroxidase \n(GPx) and SOD, and decreased the activity of MPO (Khedr \n2015). Consequently, it is posited that MTZ may augment \nthe antioxidant activity of the ovary and reduce the forma -\ntion of peroxynitrite, generated by the interaction between \nNO and superoxide anion. This is achieved by neutralizing \nthe superoxide anion through the action of SOD. MTZ is \nprone to causing sedation, increased appetite, weight gain, \ndry mouth, and occasionally agranulocytosis. Caution is \nwarranted with other serotonergic drugs (Nutt 2002).\nSildenafil\nErectile dysfunction and pulmonary arterial hyperten -\nsion are two conditions for which sildenafil, an inhibitor \nof phosphodiesterase type 5, is most commonly used to \ntreat. The action of sildenafil is to relax smooth muscles \nand dilate blood vessels by increasing levels of cyclic \nguanosine monophosphate, which is achieved by inhibit -\ning phosphodiesterase type 5. The mechanism that under -\npins its therapeutic benefits is the enhancement of blood \nflow to certain tissues (Kukreja et al. 2005 ). Previous \nexperimental studies have demonstrated that sildenafil \npossesses significant antioxidant effects in diabetes-\ninduced erectile dysfunction (Morano et al. 2007). Silde -\nnafil has also been investigated in ischemia–reperfusion \ninjury in ovarian tissue, and it was effective in prevent -\ning reperfusion injury after ischemia (Ganla et al. 2019; \nIncebiyik et al. 2015). Animal models demonstrated that \nsildenafil medication maintained primary follicle count \nand had no significant change in the secondary follicle \ncount, ovarian size, or AMH level (Ergin et al. 2022 ). \nSildenafil sustained normal concentrations of E2 and \nAMH, while inhibiting the elevation of FSH and LH, \noften observed in cisplatin-induced POF (Taskin et al. \n2015 ). Side effects include headache, flushing, nasal \ncongestion, visual disturbances, and, rarely, cardiovas -\ncular events, particularly in those with pre-existing heart \ndisease (Ausó et al. 2021).\nAtorvastatin\nStatins are a type of medication that are classed as \n3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibi-\ntors (Stancu and Sima 2001). ATV has an anti-inflammatory \n(Fassett and Coombes 2013) and antioxidant effect (Crevar-\nSakač et al. 2016). Low doses of ATV have been prescribed \nfor treating hyperlipidemia. On the other hand, high doses \ncan cause many complications, including nephrotoxicity \n(Nasri et al. 2016) and testicular injury (Klinefelter et al. \n2014). On the other hand, ATV does not have any adverse \neffects on fertility or reproduction when it is administered \nat low doses (Dostal et al. 1996). An increase in the levels \nof estrogen and progesterone, a decrease in the levels of \nMDA, and an increase in cell viability are all characteristics \nof ATV that have been found to have a protective impact \nagainst CP-induced ovarian damage. Additionally, ATV \nwas able to stabilize the ovarian histological structure while \nsimultaneously lowering the positivity level of caspase-3 \n(Hamzeh et al. 2018). Main risks comprise myopathy, rhab-\ndomyolysis (rare), elevated liver transaminases, and new-\nonset diabetes. ATV is contraindicated in pregnancy due to \nteratogenic potential (Thompson et al. 2016).\nAzilsartan\nAs an angiotensin II receptor antagonist, azilsartan has been \nshown to possess significant anti-inflammatory and antioxi-\ndant pharmacological effects (Perry 2012). Azilsartan treat-\nment in an animal model of CP-induced POF demonstrated \na potential protective effect via its anti-inflammatory effects, \nwhich was evidenced by increasing IL-10 levels and decreas-\ning TNF-α levels. The antioxidant effect of azilsartan pre -\nserved the structure and number of ovarian follicles after CP \nexposure (Mahmood 2024). The most typical side effects are \nhypotension, dizziness, hyperkalemia, and rare angioedema \n(Lam 2011).\nBerberine\nAn isoquinoline alkaloid that is derived from natural sources \nis berberine or BBR. Strong antibacterial, anti-inflammatory, \nanti-hypoglycemic, and antioxidant effects are displayed by \nit (Tillhon et al. 2012; Li et al. 2014). It is mostly used to \ntreat bacterial infections of the gastrointestinal system (Song \net al. 2020). BBR has also been used to treat ulcers, diabetes, \ncancer, and cardiovascular diseases, as demonstrated in a \nnumber of earlier research (Ai et al. 2021; Liu et al. 2018b). \nOvarian shrinkage, weight loss, and a reduction in ovarian \nfollicular reserve are all features of CP, which also leads \nto hormonal imbalance. However, all these discrepancies \nwere significantly improved by BBR therapy. Furthermore, \n1966 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nBBR was shown to activate the Nrf2 pathway and inhibit \nthe NF-kB pathway, hence reducing the buildup of ROS \nand mitochondrial dysregulation in ovarian tissues (Peng \net al. 2023). BBR can lower FSH levels while concurrently \npromoting the production of AMH and estrogen to enhance \novarian function. This aids in preserving a steady hormonal \nbalance (Peng et al. 2023). BBR is mostly associated with \nmild gastrointestinal discomfort at high doses (Prajwala \net al. 2020).\nCurcumin\nOne naturally occurring phytochemical that is present \nin turmeric is called curcumin (CRC) (Marchiani et al. \n2014), which has been found to have notable benefits as \nan anti-inflammatory, anti-cancer, and analgesic (Haanpää \nand Treede 2012; Beltran et al. 2007). These activities’ \nmechanisms are especially linked to their anti-inflamma -\ntory effects, which include modifying macrophage func -\ntion by lowering the production of lysosomal enzymes, \nproteases, and arachidonic acid metabolites (Shehzad et al. \n2013). Chemotherapy has been found to significantly affect \novarian reserve, causing abnormalities in hormonal shifts, \nincreased tissue oxidative stress, and increased histologi -\ncal damage. However, the levels of oxidative stress, ovarian \nreserve indicators, and histological abnormalities analyzed \nwere significantly reduced when CRC and CP were admin-\nistered together (Meirow et al. 2010; Lopes et al.  2014). \nIt has been demonstrated that the mechanisms behind the \nantioxidative and anti-inflammatory effects of CRC include \nNF-κB suppression, which reduces the production of inflam-\nmatory cytokines and inducible NOS (Menon and Sudheer \n2007). Moreover, quinone oxidoreductase 1 and glutathione \nS-transferase gene expression and the enzymatic activity of \nNAD(P)H are also upregulated by CRC (Jaja-Chimedza \net al. 2017). The oxidative stress created as a result of CP \nadministration results in ovarian failure by causing apoptosis \nand preventing the nuclear and cytoplasmic development of \noocytes (Liang et al. 2017). Tissue oxidative stress mark -\ners, including MDA, GSH, and SOD, were improved after \nCRC administration (Melekoglu et al. 2018). Furthermore, \nthere was a significant decrease in FSH and LH levels and \na significant increase in AMH and E2 levels following the \nadministration of CRC (Melekoglu et al. 2018). CRC is asso-\nciated with mild gastrointestinal discomfort at high doses. \nCurcumin may also cause allergic dermatitis in rare cases \n(Burgos-Morón et al. 2010).\nQuercetin\nMany different plants and natural foods, such as tea, kale, \napples, and onions, contain quercetin, a naturally occurring \nflavonoid (Suarez-Almazor et al. 1996). It exhibits potent \nantioxidant and anti-inflammatory properties (Boots et al. \n2008). By alleviating oxidative damage and activating mito-\nchondrial biogenesis via the peroxisome proliferator-acti -\nvated receptor gamma coactivator 1-alpha (PGC1-α) path -\nway, this drug can alleviate mitochondrial dysfunction (Chen \net al. 2022). Furthermore, quercetin has been shown to sup-\nport the maintenance of ovarian function in CP-induced POF \nby preventing the pyroptosis process (Chen et al. 2022). The \ninjection of quercetin shields the ovarian reserve from the \novarian damage brought on by CP by increasing blood levels \nof AMH and E2 while concurrently lowering levels of FSH \nand LH (Jiao et al. 2021). This resulted in an increase in ATP \nlevels as well as PGC1-α mRNA and protein expression. \nAdditionally, it was found to have anti-pyroptotic potential \nby suppressing the levels of NLRP3, caspase-1, GSDMD, \nand IL-1β in the granulosa cells (Biasizzo and Kopitar-Jerala \n2020). It is well-tolerated, with rare instances of headache, \ntingling, or renal impairment at extremely high doses (Najafi \net al. 2022).\nAll previously discussed protective agents are summa -\nrized in Table  1, which serves as a comparative table to \nillustrate the molecular target, experimental model, and key \noutcomes associated with each protective agent.\nThe summarized findings in Table 1 highlight the diverse \npharmacological and natural agents evaluated for protection \nagainst CP-induced ovarian damage. Notably, these agents \nconsistently target a core set of interconnected molecular \nmechanisms, primarily oxidative stress, inflammation, \nand apoptosis, which collectively contribute to follicular \ndepletion and POF. Oxidative stress emerges as a central \npathogenic feature, with CP metabolism generating ROS \nthat disrupt redox balance (Khallaf et al. 2023). Protective \nagents commonly enhance the antioxidant defense system, \npredominantly via activation of the Nrf2/HO-1 pathway, \nleading to upregulation of phase II antioxidant enzymes such \nas SOD and GSH (Gao et al. 2023). For example, cilostazol, \nberberine, LCZ696, and buspirone demonstrated significant \nrestoration of oxidative parameters, reducing lipid peroxida-\ntion and mitigating mitochondrial dysfunction. This anti -\noxidative effect is critical for preserving GC viability and \nfollicular integrity.\nInflammatory signaling is intricately linked with oxida -\ntive stress, where DAMPs released from injured ovarian \ncells activate TLR4 and downstream NF-κB and NLRP3 \ninflammasome pathways. This results in enhanced produc -\ntion of pro-inflammatory cytokines, including TNF-α, IL-6, \nand IL-1β (Rofaeil et al. 2025). Agents such as donepezil, \nlevomilnacipran, and moxibustion suppress these pathways \nby inhibiting TLR4/NF-κB activation and NLRP3 inflam -\nmasome assembly, thereby alleviating inflammation and \nsubsequent pyroptosis.\nApoptotic mechanisms are regulated through a delicate \nbalance of pro- (Bax, caspase-3) and anti-apoptotic (Bcl-2) \n1967Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nTable 1  Comparative effects of protective agents on cyclophosphamide-induced ovarian toxicity in preclinical models\nDrug/agent Molecular targets Experimental model Key outcomes Reference\n(s)\nBuspirone • NF-κB/NLRP3/caspase-1 pathway\n• Nrf2/HO-1 and p-AMPK signaling\n• α-Klotho protein expression\n• Bax/Bcl-2/caspase-3 apoptotic axis\nFemale Wistar albino rats were administered \na single intraperitoneal dose of 200 mg/kg \nof CP on the first day, followed by a Daily \ndosage of 8  mg/kg for the subsequent \n14 days\n• Ovarian oxidative stress markers sug-\ngested an improved antioxidant status, \ndemonstrated by lower MDA and elevated \nSOD and GSH levels\n• Lowered inflammatory cytokines (↓ TNF-\nα, IL-1β, IL-18)\n• Inhibited apoptosis (↓ caspase-3, ↑ Bcl-2)\n• Restored folliculogenesis and ovarian \nstructure\n• Improved hormone levels (↑ AMH, E2, \n↓ FSH)\n• Attenuated histopathological abnormali-\nties\nKhallaf et al. \n2025)\nLevomilnacipran • TLR4/p38-MAPK/NF-κB p65\n• Caspase-3\n• Klotho protein expression\nFemale Wistar albino rats received a single \nintraperitoneal dosage of 200 mg/kg of CP \non the first day, followed by 8 mg/kg for \nthe subsequent 14 days\n• ↓ Pro-inflammatory cytokines (TNF-α, \nIL-6)\n• ↓ Apoptotic index\n• ↑ AMH, Klotho, and estradiol levels\n• Preservation of follicular integrity\nRofaeil et al. \n2025)\nCilostazol • Nrf2/HO-1 pathway\n• Increased cyclic adenosine monophos-\nphate\nFemale rats, administered CP at a dosage of \n150 mg/kg via intraperitoneal injection as \na single treatment\n• Ovarian tissue showed decreased MDA \nlevels and increased SOD and GSH activ-\nity, indicating an enhanced antioxidant \nprofile\n• Enhanced Nrf2/HO-1 gene expression\n• Reduced ovarian apoptosis\nAbdel-Aziz et al. \n2020)\nDiosmin • Anti-oxidative and anti-inflammatory \npathways\n• Expression of miRNA-145 and its target \ngenes VEGF-B and RGC32\nSwiss albino rats were given a single intra-\nperitoneal dosage of 200 mg/kg of CP on \nthe first day, followed by 8 mg/kg for the \nsubsequent 14 days\n• Increased AMH, E2 levels\n• Reduced oxidative stress\n• Preserved ovarian histology\n• Decreased follicle atresia\nAbogresha et al. \n2021)\nDonepezil • TLR4/NF-κB/NLRP3 pathway\n• Pro-inflammatory cytokines\nFemale Swiss albino mice were adminis-\ntered CP as a single intraperitoneal dose of \n(75 mg/kg)\n• Dose-dependent increase in AMH\n• Lowered TLR4/NLRP3/IL-6/TNF-α \nexpression\n• Improved healthy follicle count\nZidan et al. 2024)\nLCZ696 • TLR4/NF-κB/NLRP3 pathway Female Wistar albino rats received a single \nintraperitoneal dosage of 200 mg/kg of CP \non the first day, followed by 8 mg/kg for \nthe subsequent 14 days\n• Markers indicative of oxidative stress \nwere altered, with decreased MDA levels \nand increased GSH and SOD activities\n• Suppressed inflammation (↓ TNF-α, \nIL-18, IL-1β, NF-κB)\n• Inhibited NLRP3/caspase-1 activation\n• Preserved ovarian reserve, improved fol-\nlicle count, and histology\n• Restored hormonal balance (↑ estradiol, \nAMH, ↓ FSH, LH)\nKhallaf et al. \n2023)\n1968 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nTable 1  (continued)\nDrug/agent Molecular targets Experimental model Key outcomes Reference\n(s)\nMelatonin • Activating the Hippo signal pathway\n• Downregulating caspase-3, Bax-mediated \napoptosis\nFemale Sprague Dawley rats were given a \nsingle intraperitoneal dosage of 50 mg/kg \nof CP on the first day, followed by 8 mg/\nkg for the subsequent 15 days\n• Preserved follicle count\n• Up-regulated cysteine-rich angiogenic \ninducer 61 and connective tissue growth \nfactor at the mRNA and protein levels\n• inhibited large tumor suppressor 1, Mps1-\nOne binder, and yes-associated protein \nphosphorylation\nXu et al. 2022a)\nFeng et al. 2022) Female mice were administered CP as a \nsingle intraperitoneal injection at a dosage \nof 75 mg/kg\n• Ovarian reserve testing and hormonal \nassays\n• Mitochondrial apoptosis pathways\n• Inhibited ovar-\nian apoptosis \nand maintained \nAMH expres-\nsion\nMoxibustion • NF-κB/TLR4 pathway\n• NLRP3 inflammasome/caspase-1\nFemale Sprague Dawley rats were given a \nsingle intraperitoneal dosage of 50 mg/kg \nof CP on the first day, followed by 8 mg/\nkg for the subsequent 15 days\n• Suppressed inflammation (↓ IL-18, IL-1β)\n• Inhibited NLRP3/caspase-1 activation\n• Restored hormonal balance (↑ estradiol; ↓ \nFSH, LH)\n• Downregulated NF-κB/TLR4 expression\nYin et al. 2023)\nResveratrol • SIRT1/Foxo3a pathway\n• Anti-apoptotic: inhibits caspase-3/Bax\nFemale Sprague Dawley rats were given a \nsingle intraperitoneal dosage of 50 mg/kg \nof CP on the first day, followed by 8 mg/\nkg for the subsequent 14 days\n• The expressions of SIRT1, Foxo3a were \nup-regulated and p53, caspase-3, and Bax \nwere down-regulated\n• Restored hormonal balance and follicular \ncount\nNie et al. 2021)\nIrbesartan • Oxidative stress and apoptosis Female rats were administered CP as a \nsingle-dose treatment at a dose of 100 mg/\nkg\n• Lowered TNF-α, MPO, and increased \nIL-10 levels\n• Decreased caspase-3, P53\n• Improved AMH, estradiol, ovarian histol-\nogy abnormalities\nAbdel-Raheem \net al. 2015)\nMirtazapine • Oxidative stress and inflammation Female rats were administered CP as a \nsingle-dose treatment at a dose of 150 mg/\nkg\n• Measurements revealed lower NO and \nMDA levels along with elevated GPx \nand SOD activities and diminished MPO \nactivity\n• Improved histopathological aberrations \nand follicular count\nKhedr 2015)\nSildenafil • AMH assay and morphometric study Female rats were administered CP as a sin-\ngle dose treatment at a dose of 200 mg/kg\n• Preserving primary follicle counts only\n• Increased AMH levels\nErgin et al. 2022)\nAtorvastatin • Oxidative stress, inflammation, and \napoptosis\nFemale rats were administered CP as a \nsingle-dose treatment at a dose of 150 mg/\nkg\n• Increased estrogen and progesterone levels\n• Mitigated acute inflammation, degenera-\ntive cells in stroma and follicles, stromal \nedema, vacuolization, atresia of the fol-\nlicles, and congestion\n• Reduced immunoreactivity level of \ncaspase-3\nHamzeh et al. \n2018)\n1969Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nproteins, governing GC survival. Apoptotic cascades are \nupregulated after CP exposure, culminating in follicular loss \n(Khallaf et al. 2025). Several agents, including resveratrol, \nquercetin, and levomilnacipran, modulate apoptosis-related \nprotein expression and caspase activity.\nParticularly, the activation of SIRT1, an NAD⁺-dependent \ndeacetylase with anti-apoptotic and anti-inflammatory \nproperties, was noted to play a key role in mitigating GC \napoptosis and promoting mitochondrial protection. Several \nagents also exhibit engagement with additional or comple -\nmentary molecular pathways that contribute to ovarian pro-\ntection (Xiu et al. 2023). For instance, levomilnacipran’s \neffects are associated with upregulation of the anti-aging \nprotein α-Klotho, which has downstream regulatory effects \non oxidative stress and inflammation. Melatonin’s protec -\ntive role involves modulation of the Hippo signaling path -\nway and regulation of autophagy via the PI3K/AKT/mTOR \naxis. Buspirone additionally activates AMPK, supporting \nmetabolic homeostasis. These auxiliary mechanisms high -\nlight the pleiotropic actions of some protective agents and \nsuggest potential synergistic therapeutic targets.\nWhile numerous pharmacological and naturally derived \nagents demonstrated promising protective effects against \nCP-induced ovarian injury in animal models, a balanced \ninterpretation of these findings necessitates consideration \nof various study limitations.\nMany preclinical studies suffer from small sample sizes \nthat limit statistical power. Detailed descriptions of rand -\nomization and blinding procedures are often missing, rais -\ning concerns about potential selection and observer biases. \nThe heterogeneity in animal species, strain, and age adds \nvariability that complicates cross-study comparisons (Spears \net al. 2019). Experimental protocols vary widely, with dif -\nferences in CP dosing schedules, timing, and duration of \nprotective agent treatment, and choice of endpoints (Kim \nand You 2021). Most studies focus on biochemical markers \n(e.g., oxidative stress parameters, inflammatory cytokines) \nand histological assessments of ovarian tissue. Functional \noutcomes such as fertility restoration and long-term ovar -\nian reserve preservation are infrequently reported. Short \nfollow-up periods hinder assessment of sustained effects \n(Ogunro and Ofeniforo 2024). The reliance on surrogate \nendpoints limits the clinical relevance of findings. Addition-\nally, animal models differ significantly from humans in CP \nmetabolism and reproductive endocrinology (Ramirez et al. \n2019). These differences challenge the direct translation of \npreclinical results. The wide range of CP dosages used in \nmodels, some exceeding clinically relevant exposures, fur -\nther complicates relevance to patient care. Addressing these \nlimitations requires rigorous study design with adequately \npowered cohorts, clearly documented randomization and \nblinding, and standardized CP and protective agent dos -\ning paradigms. Incorporating multidimensional outcome \nTable 1  (continued)\nDrug/agent Molecular targets Experimental model Key outcomes Reference\n(s)\nAzilsartan • Oxidative stress and inflammation Female rats were administered CP as a \nsingle-dose treatment at a dose of 200 mg/\nkg\n• Increased IL-10 levels and decreased \nTNF-α levels\n• Preserved the structure and number of \novarian follicles\nMahmood xxxx)\nBerberine • Nrf2/SOD/CAT \n• NF-κB, IL-6, and IL-1β\nFemale rats were administered CP as a \nsingle-dose treatment at a dose of 120 mg/\nkg\n• Activated the Nrf2/SOD/CAT pathway \nand inhibited the NF-kB pathway\n• Downregulated IL-6 and IL-1β\nPeng et al. 2023)\nCurcumin • Oxidative stress markers\n• Hormonal and histopathological assess-\nment\nFemale Wistar albino rats received a single \nintraperitoneal dosage of 200 mg/kg of CP \non the first day, followed by 8 mg/kg for \nthe subsequent 14 days\n• Reductions in MDA levels alongside \nincreases in GSH and SOD activities, sug-\ngesting an improved antioxidant profile\n• Decreased FSH and LH levels and signifi-\ncantly increased AMH and estrogen levels\nMelekoglu et al. \n2018)\nQuercetin • Expression of PGC1-α\n• NLRP3, caspase-1, and gasdermin D \nlevels\nFemale rats were administered CP as a \nsingle-dose treatment at a dose of 90 mg/\nkg\n• Upregulated PGC1-α mRNA and protein \nexpression\n• Suppressed the levels of NLRP3, \ncaspase-1, GSDMD, and IL-1β in the \ngranulosa cells\nBiasizzo and \nKopitar-Jerala \n2020)\n1970 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nmeasures, including molecular, histological, hormonal, and \nfertility metrics, and longer-term follow-up, will enhance \nunderstanding of protective efficacy and safety.\nThe protective effects observed in different animal mod-\nels are highly dependent on the specific experimental pro -\ntocols employed, particularly concerning the dose, timing, \nand administration route of the tested agents. Variations in \nthe administered dose can profoundly influence not only \nthe magnitude of observed effects but also the potential \nfor toxicity or subtherapeutic responses, thereby compli -\ncating cross-study comparisons. Similarly, the timing of \nintervention, whether administered before, concurrent with \ncyclophosphamide, may determine the extent of protection \nconferred, as it can affect the agent’s ability to precondi -\ntion tissue, interrupt ongoing damage, or promote recovery. \nMoreover, the route of administration (e.g., intraperitoneal, \nintravenous, oral, or local injection) can substantially alter \nagent bioavailability, distribution, and pharmacodynamics, \nwhich in turn impacts tissue targeting and effectiveness. \nThese variables, which often differ widely across studies, \nlikely contribute to the heterogeneity observed in outcomes \nand may restrict the generalizability of results. Future \nresearch should prioritize systematic evaluation of these \nparameters to optimize protective protocols and enhance the \ntranslational relevance of experimental findings.\nAdditionally, a limitation of the present study is its reli -\nance on available evidence from the preclinical level, which \nreported associative biochemical markers (e.g., SOD, GSH) \nto infer mechanistic protection. Although these markers are \nwell-established indicators of oxidative stress and cellular \nstatus, their improvement may be correlative rather than \ncausative regarding functional protection (Ghezzi et al. \n2017). Future investigations utilizing targeted mechanistic \ninterventions and causal experimental approaches (e.g., spe-\ncific pathway inhibitors or genetic models) are warranted to \nclarify direct cause-and-effect relationships.\nEmerging non‑pharmacological therapies: \nstem cell therapy and exosome‑based \ntherapy in POF\nStem cell therapy\nContemporary interventions such as HRT mitigate menopau-\nsal symptoms but carry considerable risks, including breast \nand endometrial cancer with prolonged usage, thromboem -\nbolism, and inability to reinstate ovarian endocrine func -\ntion or fertility (Xinyue et al. 2025). Ovulation induction \ndemonstrates limited efficacy in autoimmune-related cases, \nunderscoring the pressing necessity for regenerative strate -\ngies aimed at restoring ovarian function. Stem cells, noted \nfor their self-renewal and differentiation capabilities, may \npotentially reverse ovarian dysfunction by facilitating fol -\nliculogenesis, diminishing GC apoptosis, and augmenting \novarian angiogenesis. Their action may occur through direct \ndifferentiation or predominantly via paracrine mechanisms \nthat release growth factors and cytokines beneficial to ovar-\nian tissue regeneration (Kim and Kim 2024; Ali et al.  2022). \nPrevalent sources include bone marrow, adipose tissue, adi-\npose-derived stem cells, umbilical cord, menstrual blood, \nand synovial membrane. Autologous transplantation, utiliz-\ning the patient’s tissue, is preferred to mitigate immunologi-\ncal responses (Ali et al. 2022; Wang et al. 2022). Preclinical \nanimal studies demonstrated enhancements in hormone lev-\nels (e.g., estradiol), follicle counts, and ovarian mass in ovar-\nian injury caused by CP. Numerous minor clinical investiga-\ntions have indicated elevated AMH, reduced FSH, improved \nantral follicle count (AFC), and recovery of menstruation, as \nwell as instances of pregnancy after stem cell therapy (Kim \nand Kim 2024; Wang et al. 2022; Umer et al. 2024a). Meta-\nanalyses have validated considerable enhancement in ovar -\nian function measures and reproductive outcomes following \nstem cell transplantation (Umer et al. 2024a, 2024b). Mesen-\nchymal stem cells (MSCs) release cytokines, growth factors, \nand anti-apoptotic proteins that diminish GC apoptosis, pro-\nmote angiogenesis, and regulate inflammation. This alters \nthe ovarian microenvironment (Zhou et al. 2023). MSCs can \ndevelop into germ cell-like cells, theca cells, and oocyte-\nsupporting stromal cells in response to ovarian niche signals, \ntherefore replenishing depleted cell populations (Xinyue \net al. 2025). MSCs inhibit pro-inflammatory cytokines \n(TNF-α, IL-6, IL-17) and enhance T-regulatory cell activ -\nity, mitigating autoimmune factors associated with POF (Wu \net al.  2024). Adipose-derived MSCs are harvested through \na minimally invasive procedure. Studies in rodent models \ndemonstrated their ability to enhance follicular counts and \nrestore estrous cycles by activating the SIRT3/SOD2 path -\nway, thereby decreasing oxidative stress (Xinyue et al. 2025; \nZhou et al. 2023). MSCs from the umbilical cord enhanced \nproliferative ability; clinical investigations demonstrated \nincreased ovarian reserve, as indicated by elevated AMH \nlevels and improved pregnancy rates. Secretome abundant in \nmiR-21-5p enhances angiogenesis (Xinyue et al. 2025; Tan \net al. 2024). Despite promising findings, stem cell therapy \nencounters obstacles such as limited sample sizes in trials, \nthe absence of standardized protocols, ethical dilemmas, and \nthe necessity for long-term safety data (Kim and Kim  2024; \nWang et al. 2022).\nBone marrow mesenchymal stem cells (BMSCs)\nBMSCs improved POF via a series of coordinated mecha -\nnisms, beginning with targeted migration and homing to \ndamaged ovarian tissue. The localization of BMSCs within \novarian stroma (hilum, medulla, cortex) is mediated by \n1971Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nchemokine receptors such as C-X-C chemokine ligand-8 \nand hepatocyte growth factor (HGF). BMSCs do not dif -\nferentiate into oocytes; rather, they exert therapeutic effects \nprimarily through paracrine signaling. These cells secrete \nvarious bioactive factors, including VEGF, insulin-like \ngrowth factor-1 (IGF-1), HGF, basic fibroblast growth fac -\ntor (bFGF), and transforming growth factor (TGF-β), which \ncollectively facilitate ovarian recovery through multiple \npathways (Huang et al. 2022). Secreted IGF-1 and VEGF \ninhibit GC apoptosis through the upregulation of Bcl-2 and \nproto-oncogene (c-myc), alongside the suppression of Bax \nand cyclin-dependent kinase inhibitor 1  A (p21) (Hu et al. \n2024). MicroRNA-21 (miR-21) amplifies this effect through \nthe targeting of phosphatase and tensin homolog deleted \non chromosome ten, thus Maintaining follicular integrity. \nHGF and bFGF decrease collagen deposition and fibroblast \nproliferation, thereby alleviating ovarian fibrosis, which \nis a characteristic of POF pathogenesis. VEGF and HGF \nwork together to enhance neovascularization, thereby restor-\ning blood flow to ischemic ovarian tissue. Angiogenin and \nmembrane type 1-matrix metalloproteinase enhance nutrient \ndelivery and tissue repair. BMSCs inhibit pro-inflammatory \ncytokines, such as TNF-α and IL-1, through the secretion of \nprostaglandin E2, indoleamine-2,3-dioxygenase, and TGF-\nβ. They simultaneously enhance regulatory T-cell (Treg) \nactivity and facilitate macrophage reprogramming to an \nanti-inflammatory phenotype (IL-10), thereby reestablish -\ning Th17/Treg ratios that are altered in autoimmune POF \n(He et al. 2018).\nHuman umbilical cord mesenchymal stem cells\nHuman umbilical cord mesenchymal stem cells (HUCM -\nSCs) primarily alleviate POF through paracrine mechanisms \nrather than direct differentiation. These cells release vari -\nous bioactive factors, such as cytokines, growth factors, and \nexosomes, which together facilitate tissue repair and regulate \nthe immune system. The secreted “conditioned medium” \nreduces GCs’ apoptosis by activating survival pathways, \nincluding PI3K/AKT, and regulating factors such as granu-\nlocyte colony–stimulating factor (Deng et al. 2021). Addi-\ntionally, it enhances GCs’ proliferation, which is essential for \nfollicle Maturation. HuCMSCs enhance ovarian function by \nrestoring T Helper 1/T Helper 2 cytokine balance and modu-\nlating uterine natural killer cell expression, thereby improv-\ning endometrial receptivity. The overall outcome includes an \nincrease in healthy follicles, restoration of normal hormone \nlevels, and normalization of the estrous cycle (Shareghi-\nOskoue et al. 2021). HUCMSCs have a low risk of immune \nrejection, are easily collected, and pose fewer ethical and \ntumorigenicity concerns than other stem cell sources.\nAdipose‑derived mesenchymal stromal cells\nAdipose-derived mesenchymal stromal cells (ADMSCs) \nimprove POF through the restoration of ovarian function by \nestablishing a regenerative microenvironment, rather than \nthrough direct differentiation into oocytes. Transplanted \nautologous adipose-derived mesenchymal stromal cells are \nthought to exert therapeutic effects through paracrine sign -\naling by secreting bioactive molecules, including VEGF, \nplacental growth factor (PGF), and TGF-β (Takehara et al. \n2013). These molecules promote angiogenesis, decrease \nGCs’ apoptosis, and modulate the local immune environ -\nment. These actions facilitate the repair of compromised \novarian niches, enhance the survival of existing follicles, and \nmay activate dormant ovarian stem cells found in the tunica \nalbuginea. This activation can result in the differentiation \nof OSCs into germ cells and primitive GC nests, ultimately \ncontributing to the formation of new primordial follicles. \nThis process facilitates follicular development and ovarian \nfunction, leading to enhanced hormonal profiles, including \nreduced FSH levels, and, in certain instances, the restora -\ntion of menstruation, as evidenced by clinical studies (Mash-\nayekhi et al. 2021). Furthermore, ADMSCs alleviate oxida-\ntive damage in ovarian tissues via upregulation of protective \npathways, including SIRT1 and FOXO1 (Hu et al. 2024).\nHuman amniotic epithelial cells\nHuman amniotic epithelial cells (hAECs) mitigate POF via \na complex mechanism that includes migration, differentia -\ntion, and the restoration of the ovarian microenvironment, \nas evidenced in mouse models of chemotherapy-induced \nPOF (Zhang et al. 2020). After intravenous transplantation, \nhAECs migrate to damaged ovarian tissue, where they first \nintegrate into the ovarian stroma and later localize near fol-\nlicles, ultimately encircling oocytes. hAECs specifically dif-\nferentiate into GCs, as confirmed by the presence of human-\nspecific nuclear antigen and human follicle-stimulating \nhormone receptor expression in recipient ovaries (Zhao et al. \n2024). There is no differentiation into germ cells, indicated \nby the lack of human Markers in oocytes. The transplanted \ncells facilitate essential somatic-germ cell interactions by \noffering structural and Functional support to developing fol-\nlicles. Notably, AMH expression reemerges in primary folli-\ncles as early as 14 days post-transplantation, with a progres-\nsive increase over time, signifying the restoration of ovarian \nfunction. The mechanism entails the trans-differentiation of \nhuman amniotic epithelial cells into functional GCs, which \nfacilitate oocyte growth and follicular development. Con -\ncurrently, this process reactivates host germ line stem cells \nwithin the damaged ovary, effectively restoring the complete \n1972 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nfolliculogenesis process from primordial to antral follicle \nstages, without any indication of germ cell differentiation \nfrom the transplanted hAECs (Wang et al. 2013b).\nAmniotic fluid stem cells\nAmniotic fluid stem cells (AFSCs) alleviate POF mainly \nby inhibiting follicular atresia and promoting healthy fol -\nlicle development, rather than by directly differentiating \ninto ovarian cell lineages. This is evidenced by studies \nusing chemotherapy-induced POF mouse models in which \nAFSCs were transplanted into damaged ovaries (Lai et al. \n2013). Post-transplantation, AFSCs integrate into ovarian \ntissue and exert therapeutic effects via paracrine signal -\ning mechanisms. They secrete growth factors (e.g., TGF-β, \nVEGF, glia cell-derived neurotrophic factor) and exosomes \ncontaining beneficial miRNAs (such as miR-10a and miR-\n369-3p) that support the survival and proliferation of GCs \nand inhibit apoptosis (Xiao et al. 2016). Research indicates \nthat they secrete proangiogenic soluble factors that facili -\ntate the recruitment of endothelial progenitors and improve \nvascularization in the damaged ovarian microenvironment. \nInstead of differentiating into primitive oocytes as previ -\nously hypothesized (given the absence of progeny from \ntransplanted AFSCs), these cells operate by modulating key \ncellular processes related to follicular atresia, specifically by \nregulating the expression of genes associated with cell death \nand survival in GCs, which are crucial for follicular devel -\nopment. AFSCs exhibit expression of OCT4 and additional \npluripotency markers, while preserving a rapid self-renewal \ncapacity, maintaining a normal karyotype in long-term cul -\nture, and demonstrating low immunogenicity, which ena -\nbles them to evade immune rejection. These characteristics \nrender them especially appropriate for therapeutic applica -\ntions. Their mechanism entails the interruption of apoptotic \npathways in GCs, which have been previously identified as \na critical factor in follicular atresia. This approach fosters a \nregenerative microenvironment that sustains existing folli -\ncles, ultimately restoring ovarian function, preserving fertil-\nity, and averting further degeneration of the ovarian reserve \nin conditions of POF (Xiao et al. 2014).\nOvarian epithelial‑like cells\nOvarian epithelial-like cells improve POF via a complex \nmechanism that includes tissue integration, reduction of \nfibrosis, and restoration of hormonal balance (Bukovsky \nand Caudle  2012). This was evidenced in mouse models of \nchemotherapy-induced POF, where estrogen-sensitive ovar-\nian epithelial (OSE)-like cells derived from human-induced \npluripotent stem cells were transplanted into damaged ova -\nries. Post-transplantation, microRNA-17-3p-induced OSE-\nlike cells demonstrate successful survival and proliferation \nwithin the POF ovarian microenvironment for a minimum \nof 14 days. These cells integrate into the ovarian tissue, \nmodulating the expression of essential cellular markers by \nsignificantly increasing epithelial markers (cytokeratin 7) \nand estrogen receptors (ERβ), while concurrently decreas -\ning mesenchymal markers (fibronectin and vimentin), thus \nreversing the ovarian fibrosis associated with POF. The \nmolecular reprogramming results in structural enhancements \nsuch as increased ovarian weight, decreased atretic follicle \ncounts, and heightened mature follicle numbers, with trans-\nplanted cells successfully reinstating the ovarian microenvi-\nronment essential for follicular development. The therapeutic \nmechanism includes the reactivation of hormonal signaling \npathways, demonstrated by significantly elevated plasma E2 \nlevels in treated mice over time. Additionally, the inherent \ncapacity of OSE-like cells to express various growth factors, \nsuch as epidermal growth factors, plays a role in tissue repair \nand regeneration. These cells operate via paracrine signaling \ninstead of differentiating into new oocytes, thereby establish-\ning a supportive microenvironment that prevents existing \nfollicles from atresia and facilitates their development dur -\ning folliculogenesis. This process alleviates the pathological \nmanifestations of POF without modifying FSH levels, while \neffectively reinstating the estrogenic environment necessary \nfor normal ovarian function (Liu et al. 2013).\nExosome‑based therapy\nExosomes are nanoscale extracellular vesicles released by \nstem cells and other cell types, containing proteins, RNAs, \nand microRNAs that influence biological functions. Exo -\nsome therapy utilizes these vesicles to facilitate tissue \nrepair and anti-apoptotic effects without the incorporation \nof complete cells, perhaps providing a safer, cell-free alter -\nnative to stem cell transplantation (Kim and Kim  2024; Ali \net al.  2022). Investigations into exosome therapy for POF \nare predominantly in the preclinical phase, with encourag -\ning outcomes in enhancing ovarian function through the \nmitigation of oxidative stress and apoptosis, as well as the \nstimulation of angiogenesis and follicle maturation (Kim \nand Kim  2024; Wang et al. 2022). Exosomes mitigate POF \nby exerting anti-apoptotic activities, such as exosomal miR-\n21-5p inhibiting PTEN and caspase-3, hence decreasing GC \napoptosis. Hypoxic ADSC-exosomes enhance miR-21-3p/\nmiR-126-5p expression, hence activating the PI3K/AKT \npathway to facilitate GC survival. Promotion of angiogen -\nesis by miR-126-3p from ADSC-exosomes targets PIK3R2, \nhence improving vascularization in rat ovaries. miR-125a-3p \nenhances HUVEC migration through PTEN suppression. \nFurthermore, the mitigation of oxidative stress through miR-\n378 in ADSC-exosomes diminishes ROS levels in human \nadult low calcium temperature (HaCaT) cells, whereas the \nSIRT3/SOD2 pathways enhance mitochondrial activity \n1973Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nunder high-glucose conditions (Xinyue et al. 2025; Zhou \net al. 2023).\nHuman amniotic epithelial cell‑derived exosomes\nHuman amniotic epithelial cell-derived exosomes present \na viable therapeutic strategy for alleviating POF induced \nby chemotherapy, leveraging various synergistic mecha -\nnisms focused on their bioactive microRNA content. The \nexosomes, exhibiting a characteristic cup-shaped morphol -\nogy of approximately 100 nm in diameter and positive for \nexosomal markers Alix, CD63, and CD9, are secreted by \nhuman amniotic epithelial cells, which demonstrate stem \ncell–like properties such as low immunogenicity and immu-\nnomodulatory capabilities (Zhang et al. 2019). In mouse \nmodels of chemotherapy-induced POF, the transplantation \nof human amniotic epithelial cell-derived exosomes admin-\nistered both directly into damaged ovaries and systemically \nsubstantially enhances ovarian function by augmenting the \nquantity of healthy primordial, primary, secondary, and \nmature follicles, which are otherwise diminished by chemo-\ntherapeutic agents. The main mechanism by which hAEC \nexosomes facilitate their restorative effect is through the \ninhibition of GCs’ apoptosis, a characteristic of chemother-\napy-induced ovarian damage (Geng et al. 2023). Exosomes \nfacilitate the transfer of functional miRNAs, particularly \nmiR-1246, into GCs. Within these cells, the miRNAs \ndownregulate apoptotic Markers, including cleaved caspase \n3 and pro-apoptotic proteins such as Bax, while simulta -\nneously upregulating anti-apoptotic proteins like Bad and \nBcl2. This molecular modulation maintains GCs’ viability \nand supports follicular integrity. Simultaneously, hAEC \nexosomes increase the expression of cumulus expansion-\nrelated genes, including hyaluronic acid synthase 2 and \npentraxin 3, which are essential for oocyte nourishment and \nfollicular development. In addition to promoting cellular \napoptosis, hAEC exosomes mitigate acute vascular injury \nin the ovary caused by chemotherapy. This is evidenced by \nthe enhanced proliferation and maintenance of endothelial \ncells (CD34-positive), which are essential for the sustenance \nof ovarian blood supply and follicle health. Moreover, these \nexosomes partially inhibit premature activation and deple -\ntion of primordial follicles by modulating the PI3K/AKT/\nmTOR signaling pathway, which is typically hyperactivated \nby chemotherapy, resulting in follicle “burnout.” Following \ntreatment with hAEC exosomes, there is a reduction in the \nphosphorylation levels of critical proteins, including Akt \nand FoxO3a, which contributes to the preservation of ovar-\nian reserve. The miRNA cargo in hAEC exosomes targets \nvarious biological pathways, including phosphatidylinositol \nsignaling, PPARγ signaling, AMPK pathways, and apop -\ntotic processes, as demonstrated by microarray and bioin -\nformatics analyses. The pathways collectively contribute to \nmetabolic regulation, anti-inflammatory effects, and tissue \nremodeling, thereby enhancing ovarian restoration. Tran -\nscriptomic analyses of treated ovarian tissue confirm the \nreversal of gene expression alterations induced by chemo -\ntherapy, aligning with enhanced metabolic functions and \ndiminished inflammatory responses. In vitro experiments \ndemonstrate the effective internalization of hAEC exosomes \nby human granulosa tumor cells and their ability to transfer \nmiRNAs that inhibit chemotherapy-induced apoptosis and \nrestore cellular function. The continuous release of miR -\nNAs, including miR-1246 and miR-21-5p, correlates with \nthe suppression of apoptosis-related proteins, highlighting \nthe therapeutic potential of exosomal miRNA cargo (Geng \net al. 2023).\nBone marrow mesenchymal stem cell‑derived exosomes\nBone marrow mesenchymal stem cell–derived exosomes \n(BMSC exosomes) alleviate POF primarily by delivering \nspecific miRNAs, particularly miR-144-5p, which demon -\nstrates anti-apoptotic effects on ovarian GCs affected by \nchemotherapy (Yang et al. 2020). In POF models induced \nby CP, treatment with BMSC exosomes significantly \nrestores ovarian function, as indicated by the normaliza -\ntion of estrous cycles, an increase in healthy basal and sinus \nfollicles, and improved serum hormone profiles, including \nelevated E2 and AMH, alongside decreased levels of FSH \nand LH. BMSC exosomes are internalized by damaged \nGCs, wherein the transferred miR-144-5p directly targets \nthe tumor suppressor gene PTEN, which negatively regulates \nthe PI3K/AKT signaling pathway (Huang et al. 2022). The \ninhibition of PTEN by miR-144-5p results in the activation \nof the PI3K/AKT signaling pathway, thereby enhancing cell \nsurvival and reducing apoptosis. Decreased expression of \napoptotic Markers, including caspase 3 and caspase 9, along \nwith reduced rates of GC apoptosis in vitro and in vivo, \nfollowing exosome treatment, supports this observation. \nFunctional assays confirm that the overexpression of miR-\n144-5p enhances the protective effects of BMSC exosomes \nagainst GC apoptosis, whereas the inhibition of miR-144-5p \nreverses these benefits. Blocking exosome release from \nBMSCs significantly reduces their ability to prevent GC \napoptosis, indicating that exosomal miR-144-5p plays a cru-\ncial role in the therapeutic effect. BMSC-derived exosomal \nmiR-144-5p preserves GCs’ viability, maintains follicular \nintegrity, and prevents follicular atresia, thereby facilitating \novarian regeneration and restoring fertility. This exosome-\nbased mechanism offers a cell-free regenerative strategy \nthat addresses challenges linked to direct stem cell trans -\nplantation, including immune rejection and tumorigenicity, \nand underscores the potential use of BMSC exosomes as an \ninnovative therapeutic approach for chemotherapy-induced \nPOF (Xinyue et al. 2025).\n1974 Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nExosomes derived from human adipose mesenchymal stem \ncells\nExosomes originating from human adipose mesenchymal \nstem cells (hADSC-Exos) alleviate POF via a complex \nmolecular mechanism that primarily involves the modula -\ntion of the homologs of Sma and Mad proteins (SMAD) \nsignaling pathway (Huang et al. 2018). Small extracellular \nvesicles encompass bioactive molecules that, when admin -\nistered in a POF mouse model or cocultured with GCs from \nPOF patients, facilitate ovarian recovery by increasing \nfollicle numbers at all developmental stages (primordial, \nprimary, secondary, and antral) and normalizing hormone \nlevels, including E2, AMH, and FSH. hADSC-Exos pro -\nmote the proliferation of GCs and significantly reduce their \napoptosis at the cellular level. This is accomplished through \nthe upregulation of key SMAD proteins SMAD2, SMAD3, \nand SMAD5, serving as intracellular effectors of the TGF-β \nsignaling pathway, which is crucial for follicular develop -\nment, oogenesis, and GCs’ function. The elevation of SMAD \nsignaling, prompted by hADSC-Exos at both mRNA and \nprotein levels, results in the downregulation of essential \napoptosis-related genes, such as Fas, Fas ligand, caspase-3, \nand caspase-8. The repression of apoptosis genes enhances \nthe survival and functionality of ovarian cells, thereby aid -\ning in the restoration of ovarian morphology and function. \nAdditionally, the knockdown of SMAD proteins via RNA \ninterference leads to an upregulation of apoptosis markers, \nthereby confirming that the therapeutic effects of hADSC-\nExos are mediated through the SMAD pathway. hADSC-\nExos function as modulators of SMAD signaling, inhibit -\ning GC apoptosis, enhancing proliferation, and restoring \nendocrine function, thus effectively alleviating POF. This \nmechanism establishes hADSC-Exos as a viable cell-free \nregenerative therapy for POF, offering benefits such as low \nimmunogenicity and enhanced safety compared to direct \nstem cell transplantation (Huang et al. 2018).\nConclusion and future perspectives\nA significant challenge to women’s health, POF can cause \ninfertility, malfunction of the endocrine system, and long-\nterm systemic issues. It is particularly concerning that CP \nmight cause harm to the ovaries since ovarian tissue is sus -\nceptible to chemotherapy medicines. As our knowledge of its \ncauses has grown, including oxidative stress, inflammation, \nand apoptosis, protective treatments have become feasible. \nSo, to develop new therapies to lessen the effects of CP-\ninduced ovarian damage, further studies are needed to assess \nother signaling molecular pathways that may be involved. \nA major challenge in translating preclinical data to clini -\ncal applications lies in the significant differences between \nanimal models and human physiology, including variations \nin ovarian physiology, follicle dynamics, hormonal regula -\ntion, and drug metabolism can lead to divergent responses \nbetween rodents and humans. For instance, the rate of pri -\nmordial follicle depletion, the sensitivity to chemothera -\npeutic injury, and the capacity for ovarian repair differ sub-\nstantially between species. Moreover, CP dosing regimens \nutilized in experimental studies often differ markedly from \nthose used in clinical practice. Animal models frequently \nemploy single high doses or repeated supraphysiological \ndoses (e.g., 100–200 mg/kg, i.p.) to induce rapid ovarian \nfailure, while human chemotherapy protocols typically \ninvolve lower fractionated doses administered over longer \nperiods. These discrepancies may exaggerate the extent and \nrapidity of ovarian damage in preclinical settings, and do not \nalways accurately predict clinical outcomes such as fertil -\nity preservation or recovery potential observed in women \nreceiving CP. Future research should address these gaps by \nadopting animal models and dosing regimens that closely \nmimic human clinical exposure, possibly using chronic, frac-\ntionated CP protocols; reporting and discussing the clinical \nrelevance of animal doses, schedules, and endpoints for each \nprotective agent; and prioritizing multi-dimensional outcome \nmeasures, including fertile potential and live birth rates over \nsurrogate biochemical or histological markers. The integra-\ntion of more clinically relevant models and study designs \nwill strengthen the translational impact of basic research \nand guide the development of effective ovarian protective \nstrategies for women undergoing CP chemotherapy.\nAuthor contributions All co-authors actively contributed to the manu-\nscript. Habiba Gamal Atta, Habiba Atef Mohammed, Nazema Shaker \nDiab, Rofaida Ashraf Atef, and Roaa Sayed Hosney participated in \ncollecting data, writing, and creating figures under the supervision of \nsenior authors experienced in reproductive toxicology, especially Prof. \nRamadan A.M. Hemeida, and Dr. Ehab E. Sharata. Additionally, Ehab \nE Sharata, Taha Bakry, Mahmoud Mohamed Omar, and Ramadan A.M. \nHemeida participated in the investigation, design, writing, reviewing, \nand editing of the manuscript. The authors confirm that no paper mill \nor artificial intelligence was used.\nFunding Open access funding provided by The Science, Technology & \nInnovation Funding Authority (STDF) in cooperation with The Egyp-\ntian Knowledge Bank (EKB).\nData availability  All source data for this work (or generated in this \nstudy) are available upon reasonable request.\nDeclarations \nConsent to participate Not applicable.\nConsent for publication Not applicable.\n1975Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985 \n\nCompeting interests The authors declare no competing interests.\nOpen Access This article is licensed under a Creative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta -\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. 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Toxicol Appl Pharmacol 116989\nPublisher's Note  Springer Nature remains neutral with regard to \njurisdictional claims in published maps and institutional affiliations.\n1985Naunyn-Schmiedeberg's Archives of Pharmacology (2025) 399:1951–1985","source_license":"CC0","license_restricted":false}