Managing the negative regulation of Sirtuins in a murine model of premature ovarian failure: focusing on the key roles of antioxidants.

Chemotherapy-associated ovarian failure (COF) refers to the impairment of both endocrine and reproductive ovarian functions after chemotherapy exposure. It is defined by the absence of regular menstruation in premenopausal females or by elevated FSH levels over 40 IU/L [ 16 ]. Chemotherapy and radiotherapy can harm the follicular reserve, the non-renewable stockpile of primordial follicles (PFs) [ 100 ].‌ The long-term effects of estrogen deficiency resulting from premature ovarian function loss on patients' quality of life and overall health should not be underestimated [ 21 ]. Available treatments that relieve sure clinical signs of this disease include hormone replacement therapy, ovulation induction therapy, and oocyte, embryo, and ovarian tissue cryopreservation, which offers minimal improvement to the endocrine and reproductive functions of the ovary and is linked to severe adverse effects. Long-term use of contraceptive steroid hormones, in particular, dramatically increases the risks of breast cancer, cardiovascular disease, and stroke [ 34 ]. The sole suggested pharmaceutical treatment for the preservation of ovarian function is the administration of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy [ 21 ]. Nonetheless, ovarian function cannot be fundamentally reinstated due to its association with numerous adverse effects [ 81 ]. All fertility preservation treatments are invasive and may increase the risk of postponing cancer treatment [ 136 ]. Excess body fat, especially abdominal obesity, is significantly associated with irregular menstrual cycles, diminished spontaneous conception, and increased risk of miscarriage, which impacts oocyte and embryo quality [ 54 ]. Caloric restriction can extend the reproductive life of females, maintain follicular reserves, and delay ovarian failure in adult rats [ 52 ]. Nonetheless, use is constrained by factors such as age, treatment urgency, and the quest for fertility-preserving medications, which poses a significant issue in oncology practice [ 100 ]. Presently, strategies possessing unique reactive oxygen species regulating characteristics, such as antioxidant drugs, hormones, and mesenchymal stem cells (MSCs), have been extensively studied and provide promising options for treatment [ 75 ]. As the introduction mentions, when the body loses its capacity to neutralize free radicals, it generates reactive oxygen species, which are vital for cellular growth and metabolism. Excessive intracellular levels of reactive oxygen species subsequently damage organelles and biomolecules, inducing varying degrees of oxidative stress in DNA, lipids, and proteins, ultimately leading to granulosa cell death through multiple mechanisms [ 33 ]. Chemotherapy agents produce ROS that disrupt the redox balance, necessitating antioxidants to re-establish this balance. Antioxidants serve to remove free radicals, neutralizing ROS [ 19 ]. Most of the antioxidants discussed in this review are small molecules that are generally administered orally. These antioxidants have attracted considerable attention from researchers for the treatment of premature ovarian failure because of their cost-effectiveness [ 5 ], minimal side effects, notable efficacy [ 47 ], dietary availability, and their ability to enhance the body's natural antioxidant system [ 137 ]. Disadvantages of using antioxidants include strong dose dependence, where high doses may cause cytotoxicity and low doses may not affect the disease. The optimal duration of use and the route of intervention (before or after disease onset) are not established [ 74 ]. Antioxidants may also interfere with chemotherapy drugs; for example, vitamin C consumption can reduce the effectiveness of chemotherapy drugs such as cisplatin [ 138 ]. In some supplements, efficacy may be limited or even harmful (for instance, high vitamin E intake can exacerbate coagulation disorders, and individual blood responses may vary due to vitamin K deficiency from malabsorption or anticoagulant therapy) [ 139 ]. Finally, personal reactions to antioxidants can differ depending on genetics, nutritional status, underlying diseases, environmental factors, and lifestyle [ 140 ]. However, these bioactive compounds can improve the female reproductive system's capacity for fertility and safeguard the ovarian reserve (Table  2 ) [ 74 ]. Antioxidants are crucial in reducing oxidative cellular damage and function as free radical removers to remove free radicals [ 19 ]. Bioactive compounds positively affect oxidative stress indicators and restore the balance between oxidative effects and antioxidant defense in POF [ 74 ]. Sirtuins influence female reproductive physiology by functioning as antioxidants against ROS. They function as the sensors and keepers of the redox environment in ovarian granulosa cells [ 20 ]. An effective treatment for premature ovarian failure involves the utilization of antioxidants that modulate the expression of Sirtuin genes and reduce oxidative stress induced by chemotherapy drugs. Mice and rats are the major animal models used in laboratories for researching POF because of their estrous cycle, which is similar to humans, though significantly shorter. Ninety-nine percent of murine genes are homologous to human genes, exhibiting significant similarities in ovarian development processes and functions and controlling the genetic pathway associated with POF between mice, rats, and humans [ 141 ]. This article aims to examine the function of sirtuin family genes in the negative control of premature ovarian failure in models made up of mice. Table 2 Advantages and disadvantages of antioxidants for the treatment of premature ovarian failure Row Advantages Reference Disadvantages Reference 1 Cost-effectiveness [ 5 ] Significant dose-dependence [ 75 ] 2 Minimal side effects, notable efficacy [ 48 ] Unclear optimal duration and intervention route [ 75 ] 3 Availability through dietary patterns (e.g., Mediterranean diet) [ 139 ] Potential interference with chemotherapy drugs [ 140 ] 4 Enhancement of the body's natural antioxidant system [ 139 ] Limited efficacy or potential harm in certain antioxidants [ 141 ] 5 Enhancement of women’s reproductive function and fertility [ 75 ] Variability in individual response [ 142 ] Advantages and disadvantages of antioxidants for the treatment of premature ovarian failure Sirtuins are members of the NAD-dependent histone deacetylase family, comprising Sirt1 and Sirt2 , which are found in both the nucleus and cytoplasm; Sirt3 , Sirt4 , and Sirt5 , which are localized to mitochondria; and Sirt6 and Sirt7 , which reside in the nucleus [ 119 ]. Sirt1 is a crucial sensor under oxidative stress conditions, coordinating cellular defense and repair mechanisms while regulating cell destiny [ 141 ]. Sirt2 regulates mitotic progression, glucose metabolism, oxidative stress response, microtubule dynamics, and chromatin alignment by the deacetylation of many targets [ 122 ]. The + NAD-dependent deacetylase Sirt3 is located in mitochondria and is crucial for mitochondrial metabolism. Sirt1 and Sirt3 are recognized as tumor suppressors [ 104 ]. Sirt4 exhibits functions as an ADP-ribosyltransferase, substrate-specific deacetylase, lipoamidase, and deacetylase [ 128 ]. Sirt5 exhibits a unique affinity for negatively charged acyl lysine modifications and initiates protein desuccinylation, demalonylation, and deglutarylation reactions [ 129 ]. Sirt6 is a chromatin-associated protein that enhances resistance to DNA damage and mitigates genomic instability in murine cells [ 132 ]. Sirt6 is intricately involved in cellular biological processes, including DNA repair, genome stability, inflammation, and metabolic homeostasis [ 142 ]. Sirt7 interacts with RNA polymerase (Pol I) and histones to regulate the transcription of rDNA, specifically during transcript elongation. The inhibition reduces transcription, stops cell proliferation, and initiates apoptosis [ 120 ]. Restricted caloric intake increases endogenous Sirt1 , which diminishes P53 expression, inhibits follicular apoptosis or atresia, and safeguards the ovarian reserve. Nevertheless, it does not alter the quantity of primary, secondary, or atretic follicles; it alone safeguards the reserves of primordial follicles [ 62 ]. Human umbilical cord mesenchymal stem cells (HUCMSC) can modulate Sirt1 expression in several disorders. Sirt1 can inhibit the function of P53 by deacetylating it at lysine 382. This inhibits and prevents apoptosis and follicular atresia [ 107 ]. Melatonin and resveratrol are recognized antioxidants that enhance ovarian function by elevating Sirt1 levels. These natural antioxidants increase the antioxidant and anti-inflammatory system [ 40 , 77 , 126 ]. Antioxidants are crucial for reactivating Sirt1 and alleviating POF symptoms. Sirt3 is essential for preserving homeostasis in oocytes, embryos, and ovaries around stress situations [ 82 ]. Sirt3 may contribute positively to folliculogenesis and luteinization in granulosa cells by sensing and regulating ROS generation. During oxidative stress, Sirt3 modifies cellular defenses to protect against ROS. It regulates SOD2 via post-translational deacetylation [ 143 ]. The upregulation of Sirt1 , Sirt2 , and Sirt3 genes reduces acetylation levels on P53, thereby preventing excessive activation of P53. This also reduces follicular apoptosis and follicular atresia. Simultaneously, the overexpression of Sirtuins inhibits P53-mediated cell cycle arrest and death [ 93 ]. Sirt5 reduces oxidative cellular damage by activating enzymes that generate NADPH. Increasing Sirt5 levels enhances the activity of SOD and GSH-Px, thereby supporting the notable antioxidative stress role of Sirt5 [ 20 ]. The prevalence and functions of Sirt5 in granulosa and cumulus cells are diminished in women with decreased ovarian reserve or reproductive age [ 82 ]. Sirt6 increases cellular NADPH levels through the direct deacetylation of NAMPT, thereby providing cellular resistance to oxidative stress damage [ 142 ]. Ergothioneine's antioxidant protection correlates with the overexpression of Sirt1 and Sirt6 , which negatively regulate NF-kB, demonstrating a robust change in control of both Sirtuins concerning redox management [ 87 ]. Sirt1 , Sirt3 , and Sirt6 expression levels in the ovaries were up-regulated in various studies under caloric restriction circumstances, but they were down-regulated following chemotherapy. Sirt2 and Sirt3 contribute to the enhancement of ovarian reserve through the upregulation of FOXO3 [ 143 ]. Research suggests that the inclusion of natural antioxidants in chemotherapy protocols may offer considerable advantages for women experiencing fertility issues. The studies indicate that Sirtuins are of significant interest as drug targets due to their redox significance, attracting substantial attention from researchers. This focus may lead to therapeutic opportunities for treating premature ovarian failure caused by chemotherapy, radiotherapy, and autoimmune drugs. Integrating antioxidants to target Sirtuins presents a promising strategy for managing secondary premature ovarian failure. In conclusion, one of the most common treatments for premature ovarian failure is the use of natural and synthetic antioxidants. Research has shown that natural compounds can improve ovarian health by promoting follicular growth, increasing egg quality, and reducing apoptosis (programmed cell death) in ovarian cells. Sirtuin family members are becoming more and more popular as a target for therapeutic interventions that aim to improve early ovarian failure, especially in cases caused by chemotherapy and radiotherapy. Antioxidant therapy, in contrast to the previously mentioned treatments, targets members of the Sirtuin family to improve ovarian function and fertility in women who have survived cancer, thereby assisting them in reaching their fertility goals. This study has several limitations: it was conducted in a murine model, which may not fully reflect human POF; the first-generation offspring were not examined, limiting the assessment of transgenerational effects; only short-term effects of antioxidants were assessed; and not all molecular mechanisms or antioxidant compounds were examined. Additionally, studies investigating the involvement of Sirt4 , Sirt5, and Sirt7 family members in premature ovarian failure are still scarce.

Reactive oxygen species are natural by-products generated during cellular metabolism, including superoxide anion, hydrogen peroxide, and hydroxyl radical. In normal cells, medium to high concentrations of ROS are associated with apoptosis as part of the cellular stress response, whereas low concentrations play a significant physiological role, influencing signaling pathways, activating transcription factors, and facilitating cell proliferation and differentiation [ 1 ]. Nearly all of the cell's subcellular organelles, including the Golgi, nucleus, endoplasmic reticulum, cytoplasm, mitochondria, and plasma membrane, produce ROS [ 2 ]. Endogenous ROS represents the primary source of DNA damage and contributes to chromosomal instability, thereby leading to the accumulation of mutations and deletions [ 3 ]. Moreover, reactive oxygen species in germ cells elevate the likelihood of genetic disorders, infertility, and miscarriage [ 4 ]. Oxidative stress is an imbalance between free radical generation and antioxidant breakdown. This redox imbalance arises from elevated ROS production and reduced antioxidant defenses. Excess ROS can induce inflammation and damage lipids, proteins, and other cellular macromolecules, resulting in oxidative stress and cellular apoptosis [ 5 ]. The antioxidative response system is deregulated by excessive oxidative stress brought on by ROS buildup, and this is strongly linked to several illnesses [ 2 ]. The administration of chemotherapeutic drugs is associated with increased ROS production, an imbalance in redox homeostasis, and impaired regulation of redox signaling pathways [ 6 ]. As a result, chemotherapeutic agents exert reproductive toxicity primarily through excessive ROS generation. This overproduction of ROS leads to structural and functional DNA damage in granulosa cells, promotes oocyte apoptosis, and reduces ovarian reserve. Together, these mechanisms play a critical role in the initiation and progression of premature ovarian failure (POF) [ 2 ]. Increased levels of ROS in the ovaries of patients with premature ovarian failure contribute to heightened oxidative stress and induce direct cytotoxic effects on granulosa cells [ 7 ]. Amenorrhea refers to the absence of menstrual periods in a female of reproductive age. Amenorrhea is separated into primary or secondary types. Primary amenorrhea is characterized by the absence of menstruation by age fifteen or three years after thelarche; secondary amenorrhea is defined as the cessation of menses for three months in a woman with previously regular cycles or six months in any woman with at least one just prior spontaneous menstruation [ 8 ]. Premature ovarian failure is a reproductive endocrine disorder that manifests in women under the age of 40 and is the leading cause of female infertility [ 9 , 10 ]. (0.1% of women under 30 and about 1% of women younger than 40) [ 11 , 12 ]. The illness is marked by raised levels of gonadotropin hormones (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)) and reduced levels of estradiol (E2), progesterone (P4), and anti-Müllerian hormone (AMH) [ 9 , 11 ]. This condition may result in enduring effects of hypoestrogenism, such as osteoporosis, cardiovascular disease, and psychiatric disorders [ 13 ]. Premature Ovarian Failure results in ovarian atrophy, reduced ovarian reserve, menstrual irregularity, mitochondrial dysfunction, and infertility in females [ 14 ]. Women with POF should be urged to sustain an active lifestyle, refrain from smoking, and keep a normal weight to mitigate the detrimental effects of hypoestrogenism [ 15 ]. Underlying factors for POF include genetics (genetic abnormalities cause 20 to 25% of POF cases) [ 9 , 11 ], Autoimmune, metabolic, and infectious causes, and approximately 80% of premature ovarian failure causes are iatrogenic, caused by treatment difficulties such as chemotherapy or radiotherapy (Fig.  1 ) [ 11 ]. The number of cases of chemotherapy-induced POF continues to grow, with approximately 70 to 100% of those receiving chemotherapy getting this disease [ 13 ]. Drugs used in chemotherapy promote apoptosis in mature ovarian follicles, make cross-links in oocyte DNA, and activate pro-apoptotic intracellular pathways [ 16 ].‌ Chemotherapy drugs harm the ovaries in several ways, including causing oogonia to fall off during pregnancy, directly reducing primordial follicles, accelerating the activation of primary follicles, inducing follicular atresia, and damaging vascular and stromal tissue, as well as causing ovarian inflammation [ 17 ]. Cyclophosphamide, an expensive and effective chemotherapy drug usually used in the treatment of several types of cancer, inflicts significant damage to the ovaries in a dose-dependent way [ 18 ]. Chemotherapy drugs such as cyclophosphamide induce ovarian toxicity, which frequently impairs normal ovarian function, resulting in uncommon inflammation, oxidative stress, apoptosis, and many other biological complications [ 7 ]. Chemotherapy drugs generate reactive oxygen species (ROS) that disturb the redox environment, needing antioxidants to restore this balance. Antioxidants function as free radical removers to neutralize reactive species [ 19 ]. Sirtuins influence female reproductive physiology by functioning as antioxidants against reactive oxygen species. They function as the sensors and keepers of the redox environment in ovarian granulosa cells [ 20 ]. Antioxidants may influence the expression of Sirtuin genes and mitigate oxidative stress induced by chemotherapy medication in the treatment of premature ovarian failure. Presenting suggested treatments and available strategies to deal with the side effects of chemotherapy drugs to POF patients during counseling seems essential [ 21 ]. This study aims to investigate how different treatments, especially antioxidants, can reactivate Sirtuin family genes to help with premature ovarian failure. It is shown that antioxidants, by increasing the expression levels of Sirtuin family genes, have the most significant impact on improving ovarian function in premature ovarian failure induced by multiple chemotherapy drugs (Fig.  2 ). Fig. 1 Designing a model for premature ovarian failure and associated therapeutic interventions: A Premature ovarian failure models using gonadotoxic drugs and radiation. B Treatment of premature ovarian failure with antioxidant therapy. The use of gonadotoxic drugs and radiotherapy drugs induces premature ovarian failure, along with various therapies that have been proposed. Still, antioxidants have received more attention than other treatment options due to their low side effects and high efficiency. Created with Biorender.com Fig. 2 Treatment methods for premature ovarian failure: A Applied clinical practice, currently used for premature ovarian failure patients, reduces symptoms to some extent. B Future potential to protect against chemotherapy-related ovarian damage, especially antioxidants, has attracted the attention of many researchers. C Regenerative strategies, that require further research and investigation. Created with Biorender.com Designing a model for premature ovarian failure and associated therapeutic interventions: A Premature ovarian failure models using gonadotoxic drugs and radiation. B Treatment of premature ovarian failure with antioxidant therapy. The use of gonadotoxic drugs and radiotherapy drugs induces premature ovarian failure, along with various therapies that have been proposed. Still, antioxidants have received more attention than other treatment options due to their low side effects and high efficiency. Created with Biorender.com Treatment methods for premature ovarian failure: A Applied clinical practice, currently used for premature ovarian failure patients, reduces symptoms to some extent. B Future potential to protect against chemotherapy-related ovarian damage, especially antioxidants, has attracted the attention of many researchers. C Regenerative strategies, that require further research and investigation. Created with Biorender.com Embryo cryopreservation has long been the preeminent method for preserving female fertility (Fig.  2 A). Since the inaugural birth resulting from in vitro fertilization embryo transfer (IVF-ET) in 1978, IVF-ET technology has advanced for almost 40 years [ 22 ]. The two primary cryobiological methods are vitrification freezing and slow freezing, which successfully reduce crystallization and cell damage brought on by ice crystal formation and cold-induced injury during the freezing process [ 23 ]. Long-term cryopreservation of oocytes does not adversely affect live birth outcomes significantly. This method is unsuitable for prepubertal girls or women without a partner due to the requirement for ovarian stimulation. This method is challenging to apply in aggressive cancers, necessitating prompt treatment [ 24 ]. Ovarian tissue cryopreservation (OTC) and ovarian tissue cryopreservation and transplantation (OTCT) represent the sole fertility options for prepubertal girls. They are considered the optimal choice for patients receiving radiotherapy and chemotherapy (Fig.  2 A). OTC administration is permissible at any point in the menstrual cycle without postponing anticancer treatment [ 1 ]. Ovarian tissue sampling and cryopreservation are conducted for preservation before the initiation of chemotherapy. Three methods exist for the removal of ovarian tissue: biopsy of the ovarian cortex, partial oophorectomy, and complete oophorectomy. Following cancer treatment, the cryopreserved ovarian tissue is thawed and placed on the ovarian surface or implanted in the peritoneum [ 24 ]. Ovarian tissue transplantation preserves normal hormonal function, restores reproductive fertility, and offers additional health benefits, including bone, cardiovascular, and endocrine improvements. In both mouse and human models of hematologic malignancies, low levels of cancer following ovarian retransplantation result in cancer recurrence [ 25 , 26 ]. Ovarian tissue transplantation results in ischemia and oxidative stress, causing a loss of 50% to 90% of primordial follicles due to ovarian damage [ 27 , 28 ]. Another disadvantage of this procedure is the difficulty of freezing the entire ovary, as extracellular ice formation occurs during the process, particularly intravascular ice formation, which could destroy the whole ovarian tissue [ 24 ]. Long-term hormone replacement therapy (HRT), which uses estrogen, progesterone, melatonin, and other hormones to alleviate menopausal symptoms caused by POF, is the current preferred treatment (Fig.  2 A). Hormone replacement therapy can be delivered via multiple techniques, and the dosing method gets more personalized [ 29 ]. This therapeutic strategy seeks to mitigate symptoms and restore hormone levels to a physiologically optimal range until the typical age of natural menopause (50–51 years) is attained [ 23 ]. HRT helps alleviate symptoms associated with low estrogen, such as vaginal dryness, hot flashes, and genitourinary tract atrophy, but it does not significantly enhance ovarian reproductive performance [ 30 ]. HRT may confer neuroprotective benefits when administered around the menopausal transition; conversely, it may have adverse effects and elevate the risk of cognitive impairment in older women [ 31 ].‌ HRT has significant side effects, including prolonged injections of contraceptive steroid hormones, which markedly elevate the risk of breast cancer and endometriosis [ 32 , 33 ]. And is associated with cardiovascular diseases and stroke [ 12 , 34 ]. Cytotoxic drugs induce follicular apoptosis, resulting in diminished estrogen and inhibin levels, which therefore elevate FSH levels that promote the recruitment of primordial follicles, known as the "burn-out effect of chemotherapy" [ 21 ]. Gonadotropin-releasing hormone (GnRH), or luteinizing hormone-releasing hormone (LHRH), is a peptide hormone that facilitates the secretion of gonadotropins (FSH and LH) (Fig.  2 A) [ 35 ]. GnRHa effectively suppresses ovarian follicles, safeguarding oocytes before chemotherapy and decreasing FSH levels [ 36 ]. GnRHa substantially diminishes the likelihood of premature ovarian failure in women under 40 years undergoing chemotherapy for primary breast cancer [ 37 ]. GnRHa mitigates chemotherapy-induced premature ovarian failure during the initial year post-treatment; nevertheless, it appears to have no impact on the resumption of menstruation or the incidence of spontaneous conception [ 22 ]. The treatment of GnRH analogs during chemotherapy markedly decreased the incidence of premature ovarian failure in young cancer patients, although it did not have protective benefits on fertility [ 31 ]. GnRH agonists typically lack protection against radiation-induced gonadotoxicity [ 38 ]. The anti-Müllerian hormone (AMH) is a ligand of the TGF-B family, exclusively produced and secreted by the granulosa cells of ovarian follicles during the initial phases of follicular development (Fig.  2 B). Anti-Müllerian hormone can preserve the follicular reserve in certain forms of ovarian injury, such as early ovarian failure induced by chemotherapy [ 39 ]. It also serves as a marker for ovarian damage [ 40 ]. It has been proposed that AMH can inhibit the activation of primordial follicles in murine models, both in vivo and in vitro. This indicates that this hormone is applicable for treating gonadal damage generated by cyclophosphamide [ 41 ]. Incorporating GnRHa can elevate AMH levels and mitigate the impact of premature ovarian failure [ 21 ]. AMH has few side effects, as it is an endogenous hormone with actions confined to the ovaries [ 38 ]. Anti-Müllerian hormone, a neuropeptide involved in life regulation, induces neuronal activity in several brain regions [ 22 ]. In cancer survivors experiencing premature ovarian failure due to gonadotoxic agents, there seems to be no acceleration in the ratio of primary follicles to developing follicles (functional ovarian reserve) as indicated by AMH levels [ 42 ]. To date, multiple studies have assessed the protective effects of several anti-DNA damage chemicals against chemotherapy-induced depletion of primordial follicles in the ovary, including casein kinase 1 (CK1) inhibitors, p53 upregulated modulator of apoptosis (PUMA), Phorbol-12-myristate-13-acetate-induced protein 1(NOXA), and imatinib [ 16 ], which are frequently utilized in cancer therapy (Fig.  2 B) [ 43 ]. Imatinib protects the ovary from damage caused by cisplatin by blocking c-Abl, a tyrosine kinase (TKI) that increases the accumulation of p63, which is the oocyte-specific homolog of p53. When DNA damage levels get too high, p63 causes cells to die. Imatinib, a tyrosine kinase inhibitor, can lessen cisplatin's damage to the ovaries by blocking c-Abl. However, it doesn't offer much protection against the damage that doxorubicin causes [ 44 ]. Nevertheless, additional studies indicated that imatinib did not prevent the removal of primordial follicles resulting from cisplatin exposure [ 45 , 46 ]. Due to the restricted practical application of this approach, the following research should focus on the safety considerations of these inhibitors [ 22 ]. Mitigating the death of ovarian granulosa cells is a crucial method for addressing POF [ 47 ]. Sphingosine 1-phosphate (S1P) and its analogs, including FTY720, may influence chemotherapy-induced oocyte death, while the elevation of ovarian sphingosine-1-phosphate mitigates ovarian follicle depletion (Fig.  2 B) [ 37 ]. It increases vascularization and angiogenesis and reduces primordial follicle apoptosis [ 38 ]. GnRHa may contribute to upregulating the anti-apoptotic sphingosine 1-phosphate, which stimulates the ceramide pathway implicated in chemotherapy-induced apoptosis in ovarian cells [ 21 ]. A study revealed that the pregnancy rate of female mice after radiotherapy improved when pretreated with S1P, enhancing ovarian function in vivo [ 48 ]. Conversely, another study indicated that sphingosine 1-phosphate administration did not mitigate the impact of chemotherapy on sarcoma cells in vitro [ 22 ]. A significant disadvantage of utilizing sphingosine 1-phosphate is the necessity for injection into the ovarian bursa, a challenging and complex procedure [ 49 ]. Excessive fat can result in menstrual irregularities, anovulation, sub-fecundity, and infertility, highlighting the adverse effects of obesity on female reproductive functions [ 50 ]. Caloric restriction is the sole non-genetic intervention that prolongs lifespan and mitigates age-related physiological deterioration across species from yeast to mammals (Fig.  2 A) [ 51 ]. Moreover, calorie restriction extends the female reproductive lifespan by preserving follicular reserve and postponing ovarian failure in adult mice [ 52 , 53 ]. A restricted-calorie diet does not influence ovarian weight or the quantity of secondary and antral follicles; altering eating habits to achieve an optimal weight is challenging [ 54 ]. Mesenchymal stem cells (MSCs) are multipotent stem cells that are readily accessible and exhibit low immunogenicity (Fig.  2 C) [ 55 ]. MSCs are adult stem cells extracted from many tissues, such as bone marrow, adipose tissue, menstrual blood, umbilical cord, amniotic fluid, and placenta. Treatment with mesenchymal stem cells has significantly advanced [ 56 ]. MSCs may reduce follicle-stimulating hormone (FSH) levels, elevate estradiol (E2) levels, and enhance follicular proliferation, thereby enhancing ovarian quality in individuals with premature ovarian failure, both in humans and mammals [ 30 ]. Human bone marrow mesenchymal stem cells (hBMMSCs) have significant proliferative capacity and the capability to develop into adipocytes, chondrocytes, and osteoblasts. hBMMSCs have been extensively studied for their use in tumor treatment, cartilage regeneration, and myocardial infarction management [ 55 ]. Human bone marrow-derived mesenchymal stem cells (BM-MSCs) were the initial stem cells identified to improve ovarian function and morphology in an animal model exhibiting chemotherapy-induced ovarian damage [ 57 ]. Adipose-derived mesenchymal stem cells (ASCs) are readily accessible and possess the capability to develop into many lineages [ 58 ]. Studies indicate that adipose-derived mesenchymal cells are among the most significant therapeutic cells for restoring ovarian function [ 59 ]. In recent times, advancements in biological therapy have suggested that MSCs have a crucial therapeutic role in the treatment of premature ovarian failure. Nonetheless, there exists a potential danger of immunological rejection following allogeneic MSC transplantation. Moreover, the autotransplantation of mesenchymal stem cells encounters challenges related to the invasive nature of the procedure and the limited availability of aged tissue sources [ 60 ]. MicroRNAs (miRNAs) are a category of short, non-coding RNAs that play a pivotal role in regulating genes and significantly impacting cellular activity, proliferation, and development, hence influencing steroidogenesis, gonadal development, ovulation, apoptosis, and corpus luteum formation (Fig.  2 B) [ 61 ]. MicroRNAs significantly influence pathways associated with anticancer treatment resistance, such as modulating responses to traditional chemotherapeutics like cisplatin and microtubule-targeting medicines [ 62 ]. miR-644-5p, delivered by bone marrow MSC (BMSC)-derived exosomes, decreased the death of ovarian granulosa cells by targeting p53, indicating that miR-644-5p may have therapeutic potential for POF and the restoration of ovarian function [ 63 ]. Overexpression of miR-126-3p can enhance the restoration of compromised ovarian morphology and functionality by promoting angiogenesis and reducing OGC apoptosis in the context of chemotherapy-induced POF [ 64 ]. MicroRNAs may serve as a promising avenue for discovering novel methods to safeguard the female reproductive system in the context of malignancies. Nevertheless, miRNAs exhibit a complex and unpredictable mechanism for reaching their target organ [ 22 ]. The artificial ovary (AO) is a new experimental device designed to generate mature oocytes suitable for in vitro fertilization (IVF) via an ex vivo multistep approach, encompassing consecutive in vitro cultures of ovarian tissue, follicles, and oocytes (Fig.  2 C) [ 65 ]. AO technology relies on the extraction of follicles from the ovarian cortex (either fresh or thawed post-cryostorage) and their subsequent embedding in an artificial matrix aimed at preserving their viability and ensuring functional activity (gametogenesis and hormonal secretion) after grafting the AO to the patient [ 58 , 66 ]. This approach necessitates a biocompatible scaffold, displays few inflammations, supports neoangiogenesis, and is biodegradable post-transplantation. Consequently, it addresses the two primary transplantation issues (post-operative graft rejection and ischemic injury) and facilitates follicular growth and migration [ 67 ]. The artificial ovary may recover gonadal hormone activity without reintroducing cancer cells, presenting a significant advantage over alternative fertility preservation techniques such as ovarian tissue transplantation; however [ 68 ], a standardized definition of an artificial ovary remains absent, and this treatment has only been conducted in animal models, with no artificial ovary transplantation executed in humans to date [ 24 ]. The concept of “antioxidant” is defined as compounds that can inhibit or neutralize free radicals before they damage the cells [ 69 ]. Antioxidants, despite their advantages and disadvantages (Table  2 ), represent a distinct category of compounds that can be further subdivided based on different criteria: enzymatic and non-enzymatic antioxidants according to bioactivity, water-soluble and fat-soluble antioxidants according to solubility, small and large molecules according to size, and endogenous or exogenous antioxidants depending on their source [ 70 ]. As mentioned, the classification of antioxidants can be done based on size, separating antioxidants into small and large molecules [ 71 ]. Small molecules are organic compounds that are typically hydrophobic and have a low molecular weight. Because of these characteristics, they can target intracellular molecules and diffuse easily across cell membranes, which helps to regulate cell activity [ 72 ]. Small molecules such as secondary metabolites, including lipids, glycosides, alkaloids, and natural phenols, are also included [ 73 ]. Research using animal models suggests that substances such as polyphenols, flavonoids, saponins, alkaloids, nicotinamide mononucleotide, etc., exhibit anti-inflammatory, antioxidant, antiproliferative, apoptosis-inducing, and reproductive protective properties. These qualities may aid in preserving ovarian reserve and enhancing reproductive potential, thus recently being regarded as an innovative strategy in the management of premature ovarian failure [ 74 ]. Another way to classify the antioxidant defense system, based on biological activity, is into enzymatic and non-enzymatic antioxidants [ 71 ]. In vivo, enzymatic antioxidants, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), are essential for maintaining reactive oxygen species balance within the organism [ 75 ]. The non-enzymatic antioxidant system comprises compounds including glutathione (GSH), vitamins C and E, melatonin, alpha-lipoic acid, and many others to differentiate antioxidants. These compounds neutralize free radicals, offering additional protection against oxidative stress. These two mechanisms collectively establish an extensive defense network, enabling cells to maintain homeostasis and avert oxidative damage during stressful conditions [ 76 ]. Extensive research spanning nearly thirty years on dietary antioxidants and their efficacy and immunogenicity during chemotherapy has revealed that small molecules with antioxidant properties, such as resveratrol (natural phytoalexin found abundantly in grapes, mulberry fruit, and various other plants) [ 40 , 77 – 79 ], melatonin [ 80 , 81 ], quercetin (flavonoid often found in fruits, vegetables, olive oil, red wine, and tea) [ 82 ], Protocatechualdehyde (natural phenolic component of salvia miltiorrhiza bunge) [ 83 ] and nicotinamide mononucleotide (NMN) [ 84 ] etc., can aid in replenishing the body's natural antioxidants, which are frequently diminished post-chemotherapy, and mitigate the adverse effects of cytotoxic agents, including chemotherapy-induced premature ovarian failure (Figs.  1 B and 2 B) [ 85 ]. Antioxidants serve as a crucial instrument for the prevention and management of premature ovarian failure, especially natural antioxidants, which have considerable therapeutic potential for POF owing to their prevalence and beneficial qualities [ 47 ]. Stimulating intracellular enzymes is essential to mitigate reactive oxygen species and protect different tissues from damage [ 86 ]. These compounds substantially enhance the function of premature ovarian failure by mitigating reactive oxygen species and activating the body's essential antioxidants while also influencing histone-modifying genes, specifically the Sirtuin family. Members of the Sirtuin family, particularly Sirt1 , can indirectly affect the antioxidant defense mechanisms of different cells through several key variables [ 87 ]. Epigenetic modifications can induce transient or inheritable changes in gene expression. Epigenomic modifications are reversible and influence gene expression in several ways without directly altering the DNA sequence. Epigenetic alterations are classified as DNA modifications, RNA modifications, histone modifications, and alterations regulated by non-coding RNAs [ 88 ]. Histone modifications represent covalent posttranslational epigenetic alterations that modify chromatin structure and, in turn, influence gene expression. Histones facilitate the compaction of DNA into nucleosomes, which are small structural units located within the nucleus. Histones consist of octamers formed by two copies of H2A, H2B, H3, and H4, which encapsulate DNA and a linker histone (H1). Chemical modifications of histone tails, including acetylation, methylation, phosphorylation, and ubiquitination, modify the affinity of chromatin for transcription factors, consequently affecting gene transcription and cellular phenotypes [ 11 , 89 ]. The initial chromatin modifications recognized were the acetylation and deacetylation of specific lysines in the N-terminal tail of histones H3 and H4. The modifications are regulated by two separate types of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). The equilibrium between the activities of these enzymes is essential for regulating chromatin in response to environmental changes [ 90 , 91 ]. Histone deacetylases (HDACs) have been divided into three classes. Class I members (HDACs 1, 2, 3, 8, 11) function as transcriptional co-repressors and are homologous to yeast RPD3. Members of HDAC class II (HDACs 4, 5, 6, 7, 9, 10) have domains analogous to yeast HDA1. Class III histone deacetylases (Sirtuins) exhibit structural differences from class I and II HDACs [ 92 ]. Protein deacetylation, recognized as a posttranslational modification, was first observed in the alteration of histones to inhibit gene transcription. Lysine-residue deacetylation is currently acknowledged as an effective mechanism by which cells react to intracellular and extracellular stimuli, having a role in cellular signaling cascades [ 93 ]. Histone-modifying enzymes undergo significant alterations during various phases of ovarian development, and resulting chromatin remodeling modifies the expression of genes that regulate ovarian function [ 94 ]. Members of the Sirtuin (Sirt) gene family are classified as histone deacetylases class III (HDAC III) [ 95 ]. Sirtuins are NAD-dependent deacetylases that exhibit excellent conservation from bacteria to humans. The sirtuin family in animals consists of seven proteins (Sirt1–Sirt7), differing in tissue selectivity, subcellular location, enzymatic activity, and targets (Fig.  3 ) [ 96 ]. Sirt1 and Sirt2 are present in both the nucleus and cytoplasm; conversely, Sirt3 , Sirt4 , and Sirt5 are solely located in mitochondria [ 97 ], and Sirt6 and Sirt7 are confined to the nuclear compartment [ 98 ]. Sirt1 , Sirt3 , Sirt5 , and Sirt6 are markers for defining normal and pathological follicular development compared to other Sirtuins [ 99 ]. The role of Sirt1 within the Sirtuin family is the most frequently studied in mammalian health [ 90 ]. Fig. 3 Subcellular localization of sirtuin family members and their function as epigenetic modifying enzymes: Sirt1 and Sirt2 are located in the nucleus and cytoplasm, and Sirt3 , Sirt4 , and Sirt5 belong to mitochondria. Additionally, Sirt3 and Sirt5 may also exhibit function inside the nucleus. Sirt6 is located in the nucleus and occasionally in the cytoplasm, while Sirt7 is in the nucleus. Created with Biorender.com Subcellular localization of sirtuin family members and their function as epigenetic modifying enzymes: Sirt1 and Sirt2 are located in the nucleus and cytoplasm, and Sirt3 , Sirt4 , and Sirt5 belong to mitochondria. Additionally, Sirt3 and Sirt5 may also exhibit function inside the nucleus. Sirt6 is located in the nucleus and occasionally in the cytoplasm, while Sirt7 is in the nucleus. Created with Biorender.com Sirt1 has been reported to be a major regulator of cellular functions, including gene expression, energy metabolism, differentiation, apoptosis, DNA repair, senescence, and oxidative stress response. Mild oxidative stress conditions have been shown to stimulate Sirt1 expression, hence influencing the targets involved in the adaptive response. Conversely, exposure to severe oxidative stress leads to heightened proteasomal degradation and enzyme inactivation of Sirt1 , resulting in diminished survival [ 100 ]. Sirt1 deacetylates histone H3/H4 and non-histone substrates, including FOXO3a, P53, NF-κB, NRF-2, and PGC-1a [ 80 ]. Sirt1 deacetylates histone 4 lysine 16 (H4K16) and histone 3 lysine 9 (H3K9), increasing heterochromatin formation via the deacetylation of histone 1 lysine 26 (H1K26) [ 20 ]. Under different physiological circumstances, Sirt1 deacetylates the Lys382 residue located at the C-terminal of P53. This deacetylation process inhibits p53-induced apoptosis by promoting P53 ubiquitination [ 101 , 102 ]. Sirt1 has a significant substrate, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1-α), which serves as an activator of mitochondrial biogenesis and a crucial regulator of mitochondrial gene expression, essential for keeping energy requirements during cellular stress factors. The Sirt1 -mediated regulation of PGC1-α activity primarily governs the expression of oxidative stress-related genes, such as glutathione peroxidase (Gox), catalase (CAT), and superoxide dismutase (SOD) [ 98 ]. Sirt1 facilitates the intracellular localization of FOXO3a via deacetylation. Sirt1 safeguards mature mouse ovarian oocytes by employing a protective mechanism against reactive oxygen species through the FOXO3a/SOD2 pathway [ 20 ]. FOXO3a is a transcription factor that modulates the expression of antioxidant genes, including superoxide dismutase 2 (SOD2) and CAT [ 103 ]. Sirt1 interacts with the RelA/p65 subunit of NF-κB and inhibits transcription through the deacetylation of RelA/p65 at lysine 310 [ 104 ]. Activation of Sirt1 inhibits NF-κB activity and subsequently reduces proinflammatory cytokines [ 40 ]. NRF-2 is essential for maintaining redox balance and regulates the expression of downstream antioxidant enzymes, including HO-1, which protects cells from damage due to excessive reactive oxygen species [ 74 ]. Sirt1 , a downstream regulatory molecule of HO-1, can help with the symptoms of premature ovarian failure by increasing the expression of Sirt1 (Figs.  4 and 5 ) [ 105 ]. Fig. 4 The association of Sirt1 with ovarian health: Antioxidants significantly affect the expression of the Sirt1 gene, which regulates the equilibrium between the antioxidant system and oxidative stress. Sirt1 improves the expression of genes critical to ovarian health while preventing the expression of genes associated with ovarian damage, inhibiting reactive oxygen species, follicle apoptosis, DNA double-strand breaks, mitochondrial damage, and oxidative stress. Created with Biorender.com Fig. 5 Intracellular signaling pathways in normal, disease, and treatment: A Normal cell: Normal cells possess just a tiny amount of reactive oxygen species, which stimulate intracellular pathways and antioxidant enzymes due to increased expression of the Sirt1 , Sirt3 , and Sirt6 genes. B Diseased cell: The application of chemotherapy and radiotherapy leads to the elevation of reactive oxygen species in injured ovarian cells, which deactivates antioxidant pathways and subsequently inhibits the expression of the Sirt1 , Sirt3 , and Sirt6 genes. C Treated cell: Appropriate therapeutic methods, including natural antioxidants, modulate reactive oxygen species levels, antioxidant pathways, and the expression of Sirt1 , Sirt3 , and Sirt6 genes. Created with Biorender.com The association of Sirt1 with ovarian health: Antioxidants significantly affect the expression of the Sirt1 gene, which regulates the equilibrium between the antioxidant system and oxidative stress. Sirt1 improves the expression of genes critical to ovarian health while preventing the expression of genes associated with ovarian damage, inhibiting reactive oxygen species, follicle apoptosis, DNA double-strand breaks, mitochondrial damage, and oxidative stress. Created with Biorender.com Intracellular signaling pathways in normal, disease, and treatment: A Normal cell: Normal cells possess just a tiny amount of reactive oxygen species, which stimulate intracellular pathways and antioxidant enzymes due to increased expression of the Sirt1 , Sirt3 , and Sirt6 genes. B Diseased cell: The application of chemotherapy and radiotherapy leads to the elevation of reactive oxygen species in injured ovarian cells, which deactivates antioxidant pathways and subsequently inhibits the expression of the Sirt1 , Sirt3 , and Sirt6 genes. C Treated cell: Appropriate therapeutic methods, including natural antioxidants, modulate reactive oxygen species levels, antioxidant pathways, and the expression of Sirt1 , Sirt3 , and Sirt6 genes. Created with Biorender.com Calorie-restricted (CR) diets significantly induce Sirt1 expression in humans and rodents [ 95 ]. A previous study indicated that a high-fat diet (20% pork fat with standard food) associated with premature ovarian failure decreases the expression of Sirt1 and Sirt6 genes; nevertheless, a caloric restriction improves the expression of Sirt1 and Sirt6  genes and mitigates the symptoms of POF [ 50 ]. Other studies indicate that POF induced by a high-fat diet (10% pork meat with a standard food) decreases the expression of Sirt1 and Sirt6 genes. However, it does not influence the estrous cycle of mice. In three dietary interventions (severe caloric restriction, moderate caloric restriction, and another type of caloric restriction), the expression of the Sirt1 and Sirt6 genes increased. This increase was most notable in the moderate caloric restriction group. The change in gene expression correlated with an improvement in the progression of premature ovarian failure [ 106 ]. The study conducted by Zhou and colleagues demonstrated that a high-fat diet (20% more fat than standard food) was employed to induce a model of premature ovarian failure. This intervention resulted in decreased expression of the Sirt1 and Sirt6 genes, which was accompanied by a reduction in FOXO3a expression and an increase in the expression of mTOR, NF-κB, and P53 genes. However, the use of caloric restriction and the simultaneous use of a specific Sirt1 activator (Sirt1720) as a treatment increased the expression of Sirt1 and Sirt6 genes. It increased the reserve of primordial follicles by reducing the expression of mTOR. The group received a caloric restriction, and Sirt1720 exhibited a reduction in NF-κB expression and decreased levels of the pro-inflammatory cytokines IL-1β and IL-6. The decline in P53 gene expression was associated with the inhibition of apoptosis in primordial follicles [ 54 ]. The overexpression of Sirt1 delays ovarian aging, while calorie restriction enhances fertility in female mice by activating Sirt1 (Table  1 ) [ 39 ]. Table 1 Types of therapeutic approaches to managing the negative regulation of premature ovarian failure by sirtuins in a murine [ 7 , 41 , 51 , 55 , 78 – 82 , 84 , 85 , 102 , 106 – 119 , 124 , 128 , 132 , 135 , 137 ] (Red color: Decreased gene expression, Green color: Increased gene expression, IP  Intra Protanal, SC  Subcutaneous, Ac  Acetylation, p  Phosphorylation, Sirt1  Silent information regulator 2 related enzyme 1, Sirt2  Silent information regulator 2 related enzyme 2, Sirt3  Silent information regulator 2 related enzyme 3, Sirt4  Silent information regulator 2 related enzyme 4, Sirt5  Silent information regulator 2 related enzyme 5, Sirt6  Silent information regulator 2 related enzyme 6, Sirt7  Silent information regulator 2 related enzyme 7, FoxO3a  Forkhead box O3, NF-κB  Nuclear factor kappa B, Nrf-2  Nuclear factor-erythroid 2-related factor 2, Nrf-1  Nuclear factor-erythroid 2-related factor 1, HO-1  Hemeoxy genase-1, BCL2  B-cell lymphoma-2, Bax  Bcl-2-associated X protein, IL-6  Interleukin-6, IL-1B  Interleukin-1beta, IL-18  Interleukin-18, mTOR  Mammalian target of rapamycin, Akt  Protein kinase B, SOD2  Superoxide dismutase 2, PGC1-α  Peroxisome proliferator-activated receptor Gamma Coactivator-1α, PPAR-γ  Peroxisome proliferator-activated receptor-gamma, CAT  Catalase, ATM  Automated teller machine, NLRP3  NOD‐like receptor protein 3, ANT2  Adenine nucleotide translocator 2, AMPK  AMP-activated protein kinase, γH2AX  H2A histone family member X, XRCC6  X-ray repair cross complementing 6, H3K9 : H3K9: Histone 3 Lysine 9, p66Shc, SHC1 SHC adaptor protein 1, OPA1  Optic atrophy 1, TFAM  Transcription Factor A, Mitochondrial) (*: Small molecules documented in Drug Bank database) Types of therapeutic approaches to managing the negative regulation of premature ovarian failure by sirtuins in a murine [ 7 , 41 , 51 , 55 , 78 – 82 , 84 , 85 , 102 , 106 – 119 , 124 , 128 , 132 , 135 , 137 ] (Red color: Decreased gene expression, Green color: Increased gene expression, IP  Intra Protanal, SC  Subcutaneous, Ac  Acetylation, p  Phosphorylation, Sirt1  Silent information regulator 2 related enzyme 1, Sirt2  Silent information regulator 2 related enzyme 2, Sirt3  Silent information regulator 2 related enzyme 3, Sirt4  Silent information regulator 2 related enzyme 4, Sirt5  Silent information regulator 2 related enzyme 5, Sirt6  Silent information regulator 2 related enzyme 6, Sirt7  Silent information regulator 2 related enzyme 7, FoxO3a  Forkhead box O3, NF-κB  Nuclear factor kappa B, Nrf-2  Nuclear factor-erythroid 2-related factor 2, Nrf-1  Nuclear factor-erythroid 2-related factor 1, HO-1  Hemeoxy genase-1, BCL2  B-cell lymphoma-2, Bax  Bcl-2-associated X protein, IL-6  Interleukin-6, IL-1B  Interleukin-1beta, IL-18  Interleukin-18, mTOR  Mammalian target of rapamycin, Akt  Protein kinase B, SOD2  Superoxide dismutase 2, PGC1-α  Peroxisome proliferator-activated receptor Gamma Coactivator-1α, PPAR-γ  Peroxisome proliferator-activated receptor-gamma, CAT  Catalase, ATM  Automated teller machine, NLRP3  NOD‐like receptor protein 3, ANT2  Adenine nucleotide translocator 2, AMPK  AMP-activated protein kinase, γH2AX  H2A histone family member X, XRCC6  X-ray repair cross complementing 6, H3K9 : H3K9: Histone 3 Lysine 9, p66Shc, SHC1 SHC adaptor protein 1, OPA1  Optic atrophy 1, TFAM  Transcription Factor A, Mitochondrial) (*: Small molecules documented in Drug Bank database) Recent studies have examined the therapeutic effects of stem cells on premature ovarian failure. Stem cells exert therapeutic effects through homing, differentiation, and paracrine stimulation mechanisms. stimulation. Stem cells spontaneously migrate to the injured ovary and are influenced by multiple variables that promote their adhesion and proliferation [ 56 ]. Recent research in this field demonstrated that cyclophosphamide-induced premature ovarian failure decreased Sirt1 gene expression and increased acetylation levels of P53 and caspase 3, resulting in increased apoptosis in primordial follicles. Conversely, the application of human umbilical cord mesenchymal stem cells (HUCMSc) enhanced Sirt1 gene expression and reduced P53 acetylation and caspase 3 activation, thereby preventing the apoptosis of primordial follicles (Table  1 ) [ 107 ]. Despite extensive research, the mechanism through which mesenchymal stem cells restore ovarian function, enhance follicular growth, and regulate immunogenesis remains unclear [ 108 ]. Antioxidants are utilized globally in investigating various diseases, attributed to their multi-pathway and multi-target capabilities, high efficiency, and reduced toxicity and side effects (Fig.  2 B) [ 47 ]. Several studies indicate the premature ovarian failure induced by doxorubicin (DOX) [ 77 ], cyclophosphamide (CTX) [ 78 ], and busulfan (BUS) [ 79 ] results in a reduction in Sirt1 gene expression by causing DNA damage and cell apoptosis. The use of resveratrol as an antioxidant enhances Sirt1 gene expression. It also modulates the expression of P53, PGC-1a, FOXO3a, and FOXO1 genes. These changes increase intracellular antioxidant enzymes such as SOD2 and support mitochondrial function under oxidative stress conditions. This process reduces the NF-κB signaling pathway, reducing reactive oxygen species and oxidative stress levels (Table  1 ) (Figs.  4 and 5 ) [ 77 – 79 ]. A study conducted by Ma et al. found that premature ovarian failure was induced by tritrigium glycosides (TG), (which are used in clinical practice for treating rheumatoid arthritis and other autoimmune diseases. Despite their significant beneficial effects, the high toxicity of TG necessitates careful evaluation and quality control for clinical use). It is associated with raised oxidative damage and apoptosis, reduced levels of intracellular antioxidants like SOD and TCA, diminished expression of BCL-2 and Sirt1 genes, and a final rise in the expression of caspase 3 and Bax. The study examined melatonin's antioxidant properties in treating POF disease. It demonstrated protective effects against POF induced by TG through the activation of the Sirt1 signaling pathway and subsequent downstream molecules, causing a reduction in oxidative stress and apoptotic damage. Results of this study indicate that melatonin does not directly eliminate most free radicals but functions as an indirect antioxidant to improve POF (Table  1 ) [ 80 ]. A different study utilized the chemotherapy agent cisplatin (CP)-induced premature ovarian failure, resulting in diminished expression of the Sirt1 /FOXO3a/BCL-2 signaling pathway. As a result, ROS and oxidative stress increased, which in turn promoted apoptosis in primordial follicles and reduced the follicular reserve. Resveratrol and melatonin worked better as antioxidants when they were combined. They increased the expression of the Sirt1 and BCL-2 genes while decreasing the acetylation of FOXO3a. These actions resulted in reduced apoptosis and follicular demise (Table  1 ) (Figs.  4 and 5 ) [ 109 ]. In another study, cisplatin induced the POF model; however, diminished Sirt1 expression resulted in enhanced AKT phosphorylation. Reactivation of Sirt1 through the antioxidant spiroheterocyclic decreased the overactivity of primordial follicles, decreased follicular apoptosis, and improved follicular reserve (Table  1 ) [ 110 ]. Numerous research studies have examined cyclophosphamide-induced premature ovarian failure, revealing diminished Sirt1 gene expression, increasing FOXO3a acetylation, and subsequently enhanced oxidative stress and ROS. Cyclophosphamide-induced premature ovarian failure is associated with decreased Sirt1 gene expression and increased P53 expression, and this causes increased follicular apoptosis levels. The intake of multiple antioxidants, including niacin [ 111 ], Zigui-Yichong-Fang [ 112 ], Danggui Shaoyao San (an herbal formulation comprising six Chinese herbs) [ 101 ] Periplaneta americana (commonly known as the cockroach is a worldwide health pest) [ 113 ], Protocatechualdehyde (a natural phenolic component of Salvia Miltiorrhiza Bunge) [ 83 ] and enhanced Sirt1 expression and modulated downstream molecules, improving cyclophosphamide-induced premature ovarian failure (Table  1 ) (Figs.  4 and 5 ) [ 83 , 101 , 111 – 113 ]. Fang, Y et al. used cyclophosphamide to induce premature ovarian failure to evaluate mitochondrial biogenesis. The study demonstrated that induced POF suppressed Sirt1 and PGC1a signaling pathways, leading to the accumulation of mtDNA mutations, mitochondrial malfunction, alterations in membrane potential, increased autophagy, and, finally, mitochondrial damage and ovarian aging. Puerarin, a natural antioxidant, improves autophagy and mitochondrial function by activating the Sirt1 /PGC1a pathway, alleviating symptoms associated with premature ovarian failure and elevated estradiol levels [ 114 ]. Classic galactosemia results from a deficit of galactose-1-phosphate uridyltransferase (GALT) caused by mutations in the GALT gene, representing the most common inborn error in galactose metabolism. In women, the shortage of GALT metabolism results in the accumulation of lactose, ultimately causing premature ovarian failure [ 115 ]. Research is concentrating on D-gal-induced premature ovarian failure, which decreases Sirt1 gene expression and consequently hinders the deacetylation of FOXO3a. This process reduces oxidative stress resistance, inhibits follicular growth and maturation, and undermines sexual maturation. However, digalactose positively influences P53 gene expression and induces programmed cell death in follicles. Natural antioxidants, such as ginsenoside Rg1 (an active component of ginseng) [ 116 ], Oyster Polypeptide [ 115 ], and Ningxin-Tongyu [ 117 ], effectively treat D-gal-induced premature ovarian failure. These substances positively influence Sirt1 gene expression, mitigate oxidative stress, and decrease follicular apoptosis, thereby alleviating the symptoms of premature ovarian failure (Table  1 ) (Figs.  4 and 5 ) [ 115 – 117 ]. Chen et al. utilized the autoimmune drug Freund’s complete adjuvant (CFA) to induce premature ovarian failure, resulting in diminished Sirt1 expression and a consequent increase in P53 acetylation. This modification caused P53 to lose its affinity for MDM2, resulting in cell cycle arrest and apoptosis, as well as a reduction in the expression of Sirt1 downstream targets, specifically HO-1 and NRF-2. A recent study utilized the antioxidant icariin, resulting in increased Sirt1 expression, subsequent increases in HO-1 and NRF-2 expression, reduced reactive oxygen species, and inhibition of P53, thus preventing apoptosis (Table  1 ) [ 105 ]. Recent research shows that POF induced by cyclophosphamide and busulfan results in inflammation, elevated reactive oxygen species, and oxidative stress, reducing Sirt1 gene expression and decreasing levels of essential antioxidants. Metformin enhanced Sirt1 expression via the AMPK/PPAR-γ/ Sirt1 pathway, increasing antioxidant capacity and enabling granulosa cells to sustain cellular homeostasis (Table  1 ) (Fig.  5 ) [ 7 ]. In a different study, POF induced by cyclophosphamide and busulfan elevated reactive oxygen species, augmented P53 activity, and promoted follicle apoptosis. The ROS produced reduces the Sirt1 gene, leading to mitochondrial damage while concurrently inhibiting ATM via TERF2 and improving apoptotic levels. Long-term use of the antioxidant Pyrroloquinoline Quinone (PQQ) and mitochondria derived from human mesenchymal stem cells (MSC-MITO) improved Sirt1 inhibition. This promoted mitochondrial biogenesis, modulated the inflammatory response, and reduced ATM phosphorylation. It also inhibited P53, thereby preventing apoptosis. (Table  1 ) [ 118 ]. A specific study utilized radiotherapy (3.2 Gy/min) to induce premature ovarian failure, resulting in increased NF-κB expression and subsequent increases in downstream inflammatory cytokines such as IL-6 and IL-8. At the same time, Sirt1 expression declined, resulting in elevated inflammation in mice with premature ovarian failure. A recent study demonstrated that the antioxidant resveratrol diminished the NF-κB pathway, inhibited irradiated radiation-induced ovarian inflammation signaling, enhanced Sirt1 expression, and alleviated symptoms of POF (Table  1 ) (Fig.  5 ) [ 40 ]. Sirt1 is the most phylogenetically similar to yeast Sir2 among the Sirtuins, becoming the most prominent and extensively researched [ 119 ]. Resveratrol was initially recognized as an activator of yeast Sir2 and was subsequently demonstrated to safeguard against age-associated infertility in mice [ 96 ]. Sirt2 includes several substrates involving both histone (H4K16) and non-histone substrates (FOXO3a, NRF-2, P53, and alpha-tubulin). Sirt2 deacetylates histone 4 lysine 16 (H4K16) and has roles in cell cycle regulation, in addition to deacetylating certain non-histone substrates, including FOXO3a and NRF-2, that contribute to oxidative stress protection (Fig.  3 ) [ 120 ]. Sirt2 has been demonstrated to acetylate FOXO3a in response to oxidative stress, an essential process in the ovary, as FOXO3a serves as a transcriptional activator of the SOD2 gene, which produces the MnSOD protein, a powerful antioxidant. Sirt2 greatly affects the modulation of the oxidative stress response [ 87 ]. A recently published survey finds that Sirt2 modulates two downstream targets of the NLRP3 inflammasome (NLRP3 and tubulin), suggesting that Sirt2 -mediated deacetylation of both proteins results in the inactivation of the NLRP3 inflammasome [ 121 ]. Sirt2 is pivotal in regulating the oxidative stress response, indicating its role in protecting organisms from metabolic disturbances via oxidative stress-dependent pathways [ 87 ]. The study by Ma et al. showed that cyclophosphamide-induced premature ovarian failure resulted in a reduction of Sirt2 gene expression, accompanied by a significant increase in the expression of NLRP3, Caspase-1, and IL-1β in the granulosa cells of patients with premature ovarian failure. Nicotinamide mononucleotide (NMN) can promote follicular development in older ovaries by diminishing follicular atresia and augmenting ovarian reserve. Elevating NAD + levels can diminish ovarian inflammation, boost oocyte quality, and improve fertility. Moreover, increasing Sirt2 can diminish NLRP3-mediated cell apoptosis and operate as an effective therapeutic for female reproductive failure (Table  1 ) [ 84 ]. Mitochondria are the organelles that contain the most significant levels of maternal genetic material, produce the majority of cellular ATP, and supply energy for chromosomal segregation or fertilization in oocytes [ 122 ]. Sirt3 is regarded as a crucial regulator of mitochondrial energy metabolism during stress by directly influencing and altering numerous processes while downregulating mitochondrial protein synthesis (Figs.  3 and 6 ) [ 123 ]. Other physiological Sirt3 substrates include FOXO3a, a transcriptional activator implicated in the cellular response to oxidative stress, and Ku70, which is involved in non-homologous end joining (NHEJ) DNA double-strand break (DSB) repair and telomere preservation [ 93 ]. Fig. 6 Different roles of mitochondrial-specific sirtuins. Created with Biorender.com Different roles of mitochondrial-specific sirtuins. Created with Biorender.com Sirt3  activates SOD2 by deacetylating lysine 122, thereby enhancing the elimination of ROS in mitochondria, and mice with elevated  Sirt3  expression exhibit higher protection against ROS [ 93 , 124 ]. Sirt3 targets metabolic enzymes within the mitochondria, such as glutamate dehydrogenase (GDH), and caloric restriction enhances deacetylase activity [ 125 ]. The premature ovarian failure model diminishes mitochondrial membrane potential (MMP) and elevates reactive oxygen species levels, resulting in mitochondrial damage and decreased oocyte quality [ 30 ]. Silencing of Sirt3 adversely impacts mitochondrial function and basal ATP production [ 93 ]. Research indicates that POF induced by nitropropionic acid (3NPA) results in diminished Sirt1 expression, subsequently leading to reduced serum GSH-px and SOD activity. Furthermore, the inhibition of Sirt1 accelerates the reduction of primordial follicles and disrupts follicle dormancy. By activating Sirt1 , resveratrol can prevent H2O2-induced apoptosis in ovarian granulosa cells via the Sirt1 /P53 pathway. Resveratrol may enhance Sirt3 expression (Fig.  5 ) [ 126 ]. In this research by Di Emidio et al., it was shown that cyclophosphamide-induced premature ovarian failure elevated the expression of Sirt1 and Sirt3 24 h post-injection. This procedure inhibited the effects of cyclophosphamide-induced ROS. The application of AS101, a synthetic antioxidant, alongside quercetin, a natural antioxidant, reduced Sirt1 and Sirt3 expression levels. Prior findings regarding cyclophosphamide-induced downregulation of Sirt1 in murine ovaries do not contradict the data presented in this research. The experiments presented in this publication primarily focused on the duration before biological harm. The reduced levels of Sirt1 reported in the previous studies may be associated with the reduction in follicle count following cyclophosphamide administration (Table  1 ) [ 123 ]. Zhang et al. relied on cyclophosphamide to induce premature ovarian failure in mice to study mitochondrial biogenesis. Induced POF caused the inhibition of Sirt3 , PGC1a, and SOD2 signaling pathways, essential regulators of mitochondrial function, and oxidative stress response to ROS. The application of human umbilical cord mesenchymal stem cells in hypoxic conditions (1% oxygen) versus normal conditions (21% oxygen) led to a decrease in cyclophosphamide-induced reactive oxygen species via the activation of the Sirt3 /PGC1a pathway, potentially aiding in the restoration of ovarian function and the preservation of fertility [ 127 ]. The enzymatic activities and substrates of Sirt4 demonstrate its critical role in regulating various cellular processes, such as carbon entry into the TCA cycle, fatty acid metabolism, and branched-chain amino acid catabolism. Sirt4 also affects electron transport chain function, reactive oxygen species generation, and mitochondrial morphology (Figs.  3 and 6 ) [ 128 ]. Sirt4 does not directly engage in DNA repair; however, it has significant enzymatic activity in countering oxidative stress produced during cellular respiration. It may protect the genome indirectly by reducing glutamate dehydrogenase activity and arresting the cell cycle [ 120 ]. Sirt4 hindered the interaction between SOD2 and Sirt3 , resulting in heightened acetylation and diminished SOD2 activity [ 87 ]. A study done by Ding et al. found that cyclophosphamide-induced premature ovarian failure resulted in increased Sirt4 gene expression. It also enhanced the activity of the apoptotic protein caspase 3 and caspase 9. This improvement was followed by reduced activity of the anti-apoptotic protein BCL-2, a significant decrease in primordial follicles, and increased cell death. Treatment with human amniotic mesenchymal stem cell-derived exosomes (hAMSC-Exos) increased the number of follicles, raised hormone levels, and enhanced oogenesis by releasing miR-320a. Additionally, there was a reduction in the expression of Sirt4 , ANT2, AMPK, and L-OPA1 genes, causing decreased ROS levels. This therapy may also play a key role in preventing glycolysis dysregulation and ROS-induced pathological disease (Table  1 ) [ 108 ]. Although direct research on the impact of Sirt4 on ovarian function remains ongoing, its participation in metabolic pathways indicates a potential role in sustaining hormonal balancing and metabolic health in women with POF. Sirt5 is recognized for its crucial functions in sustaining metabolic and cellular homeostasis by modulating many processes, such as glucose oxidation, ketone body formation, fatty acid oxidation, ammonia detoxification, and reactive oxygen species management (Figs.  3 and 6 ) [ 129 ]. Sirt5 is now believed to function as a potential regulator of redox homeostasis by initiating a multifaceted antioxidant response encompassing mitochondria and other redox-active organelles. Sirt5 regulates the redox environment by enhancing the activity of the initial antioxidant enzymes. Sirt5 desuccinylates SOD1 (also known as cytosolic CuZn-SOD), causing an increase in the removal of O₂ originating from the cell. Therefore, increased SOD1 expression significantly diminishes reactive oxygen species [ 82 ]. Glutathione peroxidases utilize reduced glutathione, GSH, to facilitate the conversion of peroxides to water. Sirt5 may directly acetylate the FOXO3a protein to enhance its localization in the nucleus. This process enhances gene expression that safeguards cells from free radicals [ 129 ]. A study conducted by Gong et al., revealed that premature ovarian failure induced by cyclophosphamide and busulfan resulted in diminished Sirt5 expression, elevated FOXO3a acetylation, and reduced antioxidant capacity. Furthermore, administering Kuntai capsules, recognized as an effective antioxidant, enhanced Sirt5 gene expression. Sirt5 promotes the nuclear localization of FOXO3a by promoting the deacetylation of its K271 and K290 residues. The deacetylation of FOXO3a enhances its expression levels by diminishing its phosphorylation and ubiquitination. Moreover, deacetylated FOXO3a protects mitochondria against ROS-induced oxidative damage by improving the activities of antioxidant enzymes, including Mn-SOD and CAT (Table  1 ) [ 130 ]. While research studies on the direct impact of Sirt5 on ovarian function are limited, its involvement in mitochondrial function and metabolic processes implies potential protective benefits against oxidative stress in ovarian tissues. Sirt6 was first identified as a nuclear ADP-ribosyltransferase. Sirt6 has been found to maintain telomeric chromatin structure and genomic integrity by the deacetylation of histone H3 lysine 9 (H3K9) (Fig.  3 ) [ 131 ]. Histone H3 lysine 56 (H3K56) has been identified as an enzymatic substrate of Sirt6 in many cell types. The deacetylation of H3K56 by Sirt6 reduces chromatin accessibility for transcription factors like NF-kB, Foxo3, and HIF1α to their target promoters, thereby decreasing the expression of their target genes [ 132 ]. Mice deficient in Sirt6 showed diminished NF‐κB activation due to H3K9 deacetylation at chromatin, resulting in cellular senescence [ 90 ]. The expression level of Sirt6 proteins correlates favorably with the size of the primordial follicle pool, potentially serving as a diagnostic for evaluating ovarian reserve [ 81 ]. A study by Shen et al. showed that digalactose-induced premature ovarian failure reduced Sirt6 gene expression and elevated H3K9 acetylation, activating the Notch signaling system and augmenting oxidative stress levels. Administration of MDL800 as a Sirt6 antagonist improved Sirt6 gene expression and diminished Notch signaling by histone H3K9 deacetylation. Sirt6 gene expression can mitigate POF and oxidative stress in granulosa cells [ 133 ]. A study by Huang et al. studied the role of Sirt6 , revealing that cyclophosphamide and busulfan-induced premature ovarian failure causes the NF-κB signaling pathway to reduce Sirt6 gene expression, resulting in ovarian damage and symptoms of premature ovarian failure (Fig.  5 B). The combined use of melatonin and autologous adipose-derived stem cells improved POF symptoms and enhanced the expression of Sirt6 genes. This process was negatively associated with NF-κB, resulting in decreased levels of IL-2 and IL-6 in the POF group (Table  1 ) [ 81 ]. Sirt7 regulates the transcription of ribosomal DNA (rDNA) via interaction with RNA Polymerase I and histones. It contributes to the stress response and cellular survival, particularly under conditions of nutritional deficiency and elevated oxidative stress, as well as in ribosome manufacturing (Fig.  3 ) [ 134 ]. Sirt7 may also inhibit cell apoptosis under stressful situations. Sirt7 may suppress the NF-κB signaling pathway, which is activated by introducing external factors into the body, hence mitigating inflammation induced by lipopolysaccharides [ 120 ]. A study by Ding et al. revealed that cyclophosphamide-induced premature ovarian failure elevated the expression of the genes Sirt7 , YH2AX (a marker of DNA damage caused by reactive oxygen species), and XRCC6, which primarily encodes the protein Ku70. This protein binds to broken DNA ends, inhibits BAX-induced apoptosis, and safeguards cells from DNA damage. Human umbilical cord mesenchymal stem cells (hUMSC-Exos) secreted exosomes that decreased the expression of Sirt7 and its target genes (PARP1, γH2AX, and XRCC6). These exosomes subsequently conveyed miR-17-5P, which reinstated POF and inhibited ROS accumulation (Table  1 ) [ 135 ].