{"paper_id":"85b2734c-798b-4548-a7d9-6746fc329f02","body_text":"Front. Biosci. (Landmark Ed) 2026; 31(1): 45414\nhttps://doi.org/10.31083/FBL45414\nCopyright: © 2026 The Author(s). Published by IMR Press.\nThis is an open access article under the CC BY 4.0 license .\nPublisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nReview\nInfluence of Oxidative Stress-Mediated Inflammation on the\nPathogenesis of Reproductive Disorders: Exploring the Benefits of\nCarnosine for Prevention and Treatment of Endometriosis\nGiuseppe Carota1,*\n , Lucia Di Pietro 1\n , Konstantinos Partsinevelos 1\n ,\nSaviana Antonella Barbati 2,3\n , Vincenzo Cardaci4\n , Andrea Graziani 2\n ,\nRenata Mangione2,3\n , Giuseppe Lazzarino 5\n , Barbara Tavazzi2,3\n , V alentina Di Pietro6\n ,\nEmiliano Maiani2,3\n , Francesco Bellia1\n , Angela Maria Amorini 1\n , Giacomo Lazzarino2,3\n ,\nGiuseppe Caruso2,3,*\n1Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy\n2Departmental Faculty of Medicine, UniCamillus—Saint Camillus International University of Health Sciences, 00131 Rome, Italy\n3Unit of Biology and Preclinical Research, IRCCS San Camillo Hospital, 30126 V enice, Italy\n4Vita-Salute San Raffaele University, 20132 Milano, Italy\n5LTA-Biotech srl, 95047 Paternò (CT), Italy\n6School of Infection, Inflammation & Immunology, Department of Inflammation and Ageing, College of Medicine and Health, University of\nBirmingham, B15 2TT Birmingham, UK\n*Correspondence: giuseppe-carota@outlook.it (Giuseppe Carota); giuseppe.caruso@unicamillus.org (Giuseppe Caruso)\nAcademic Editor: Indrajit Chowdhury\nSubmitted: 30 July 2025 Revised: 13 September 2025 Accepted: 22 September 2025 Published: 16 January 2026\nAbstract\nEndometriosis is a chronic pathological condition characterized by the growth of endometrial-like tissue outside the uterine cavity and\nis frequently associated with severe pain, persistent inflammation, and fibrosis within the pelvic region and other parts of the body. The\nexact causes of endometriosis are not clear, but an innate or adaptive immune response defect has recently been suggested as a factor in\nthe disease’s development. Carnosine is a natural dipeptide formed by the ligation of β-alanine and L-histidine and characterized by a\nmultimodal mechanism of action that includes antioxidant and anti-inflammatory activities. Carnosine has also been shown to modulate\nglucose, nucleotide, and lipid metabolism as well as the response of immune cells, all processes that play a key role in the context of\nendometriosis. Despite numerous reviews published on the structure, role, function, and biological activities of carnosine in preclinical\nand clinical settings, none have focused on its therapeutic potential for the prevention or treatment of reproductive disorders, including\nendometriosis. In this review, after a brief introduction to the pathogenesis and pathophysiology of endometriosis, we focus on the\nuse of carnosine for the management of reproductive disorders, concluding with its ability to modulate specific cellular and molecular\nmechanisms closely related to endometriosis. Given the central role of oxidative stress and inflammation across several reproductive\ndisorders, carnosine may represent a promising therapeutic candidate not only in endometriosis, but also in broader reproductive health\ncontexts.\nKeywords: reproductive health; endometriosis; carnosine; inflammation; oxidative stress; iron overload; immune system phenomena;\nmacrophage polarization; microglia; neuroprotection\n1. Introduction\nEndometriosis is a chronic, estrogen-dependent gy-\nnecological disease affecting approximately 10–15% of\nwomen of reproductive age. It is characterized by the pres-\nence of ectopic endometrial-like tissue (glands and stroma)\noutside the uterine cavity, most commonly within the pelvic\nregion, and is associated with symptoms such as dysmen-\norrhea, chronic pelvic pain, dyspareunia, and infertility\n[1]. The pathological lesions are associated with significant\nmorbidity, a detrimental impact on quality of life, and con-\nsiderable socioeconomic burden [ 2]. An increasing body\nof evidence has highlighted the pivotal role of oxidative\nstress and inflammation in the pathogenesis of endometrio-\nsis (Fig. 1) [1,3].\nOxidative stress occurs in the presence of an imbal-\nance between reactive oxygen species (ROS) and antiox-\nidant defenses, leading to oxidative damage and promot-\ning a pro-inflammatory microenvironment. In particular,\nretrograde menstruation introduces erythrocytes and heme\ninto the peritoneal cavity; their breakdown generates free\niron, which catalyzes the formation of ROS via Fenton re-\nactions, thereby damaging peritoneal tissues and contribut-\ning to lesion establishment and progression [ 1,4]. In ad-\ndition, immunologic dysfunctions, such as impaired natu-\nral killer (NK) cells clearance and the accumulation of ac-\ntivated macrophages, sustain both oxidative stress and in-\nflammation. Activated macrophages phagocytize erythro-\ncyte debris and release pro-oxidant and pro-inflammatory\n\nFig. 1. Oxidative stress and inflammation in the pathogene-\nsis of endometriosis. Oxidative stress and inflammation are key\ncontributors to the pathogenesis of endometriosis. The excessive\nproduction of reactive oxygen species (ROS) and the release of\ninflammatory cytokines create a self-perpetuating cycle that exac-\nerbates disease progression.\nmediators, which further exacerbate this pathologic cycle\n(Fig. 1) [5,6]. Given the complex interplay between oxida-\ntive stress, inflammation, and immune dysregulation, tar-\ngeting oxidative pathways represents an important strat-\negy for reducing both symptomatic burden and lesion pro-\ngression. In this context, the naturally occurring dipep-\ntide carnosine ( β-alanyl-L-histidine) emerges as a promis-\ning therapeutic agent. In fact, carnosine exhibits a robust\nantioxidant activity along with anti-inflammatory, metal-\nchelating, and anti-glycating properties. Additionally, it\nmodulates metabolic and immune processes that overlap\nsignificantly with pathogenic mechanisms implicated in en-\ndometriosis [ 7,8]. While endometriosis is the primary fo-\ncus of this review, the oxidative and inflammatory land-\nscape explored is also relevant in other reproductive dis-\norders such as polycystic ovary syndrome (PCOS) and\nmale infertility, suggesting potential broader implications\nfor carnosine-based interventions.\n2. Molecular Pathogenesis and Key\nMechanisms of Endometriosis\nUnderstanding the multifactorial etiology of en-\ndometriosis is essential to identify therapeutic targets.\nAmong the different theories, the major hypotheses ex-\nplaining lesion formation are represented by retrograde\nmenstruation, iron overload, and immune dysfunction\nlinked to oxidative stress and inflammation.\nThe most widely accepted theory of retrograde men-\nstruation and implantation, originally postulated by Samp-\nson in the 1920s, suggests that menstrual debris flows\nbackward through the fallopian tubes into the peritoneal\ncavity, allowing viable endometrial cells to implant and\nproliferate on peritoneal surfaces [ 9,10]. Although retro-\ngrade menstruation occurs in many women, the differen-\ntial progression to endometriosis is thought to depend on\nadditional factors such as iron overload and immune al-\nterations [ 11]. Retrograde bleeding delivers erythrocytes\nand heme into the peritoneal cavity; their breakdown leads\nto the accumulation of free iron, which is responsible\nfor the generation of harmful oxidative species through\nFenton reactions [ 4]. Different studies demonstrate sig-\nnificantly elevated levels of free iron and ferritin in the\nperitoneal fluid of women with endometriosis compared\nto controls, with levels correlating with disease severity\n[12–14]. In addition, ferritin-loaded macrophages in le-\nsions represent a further marker of iron deposition level.\nThe resulting iron overload and ROS production cause ox-\nidative damage, induce lipid peroxidation, and may trig-\nger ferroptosis in peritoneal and follicular cells, poten-\ntially contributing to infertility [ 15–18]. ROS accumula-\ntion damages lipids, proteins, and DNA within peritoneal\nand ectopic tissues [ 19]. Studies have demonstrated in-\ncreased oxidative biomarker levels (including malondialde-\nhyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG)) in\nperitoneal and follicular fluids of affected women [ 3,20–\n22]. Further, oxidative damage to mitochondria triggers\nmtDNA leakage, activating innate immune sensors like the\ncyclic GMP-AMP synthase-stimulator of interferon genes\n(cGAS–STING) pathway, which promotes autophagy and\nenhances the invasive and migratory capacity of ectopic\nstromal cells [23,24].\nRegarding the immunologic aspect of the disease, in\nwomen with endometriosis, immune surveillance mecha-\nnisms appear deficient [ 25,26]. Key findings include re-\nduced NK-cell cytotoxicity, altered macrophage activation,\nand an inflammatory peritoneal microenvironment [ 11,27].\nThis dysfunction impairs clearance of ectopic endometrial\ncells, promotes pro-oxidant and pro-inflammatory cytokine\nrelease (including tumor necrosis factor- α (TNF-α) and\ninterleukin-6 (IL-6)), and allows the persistence of im-\nplants, which exacerbate oxidative stress and lesion pro-\ngression [28–30]. In this context, a retrospective study con-\nducted on females with reproductive failure and a history of\nendometriosis shows that peripheral NK cytotoxicity was\nsignificantly reduced, while it was observed an increased\ninfiltration of uterine CD68 + macrophages [ 31]. The ac-\ntivity of NK cells is regulated through the signals from\ntheir receptor NK group 2D (NKG2D), which represents\nan activating C-type lectin-like NK cell receptor involved\nin the elimination of transformed cells. After the binding to\nthe related ligands, NKG2D triggers a cytotoxic response\nthat activates NK cells [ 32]. Paradoxically, it has been re-\nported that increased levels of soluble NKG2D ligands in\nthe serum of cancer patients generate an inhibitory action on\nNK cells, which seems to be related to a strategy for cancer\ncells to avoid immune surveillance [ 33]. The importance\nof NKG2D ligands in the disease pathogenesis was demon-\n2\n\n\nFig. 2. Multifactorial etiology of endometriosis. Multiple mechanisms contribute to the etiology of endometriosis. These include\nectopic implantation through retrograde menstruation, iron overload with consequent ROS generation and Fenton reactions, and immune\ndysfunctions that hinder lesion clearance. Oxidative stress further amplifies cellular damage, leading to mitochondrial DNA leakage\nthat sustains stromal cell migration via innate immune activation. Additionally, oxidative stress promotes pro-survival signaling in\nectopic cells. The resulting chronic inflammation drives tissue proliferation, angiogenesis, and fibrosis, all hallmarks of endometriosis\npathogenesis.\nstrated in a prospective study conducted on endometriosis\npatients in which increased levels of NKG2D ligands in\nperitoneal fluid were associated to a reduced expression of\nthese factors in ectopic endometrial cells surface, leading to\nan evasion from NK cells recognition [ 32]. The combined\neffects of immune dysfunction, iron-induced ROS produc-\ntion, and oxidative damage create a vicious cycle (Fig. 2).\nMacrophages play a complex and multifaceted role in\nthe development and progression of endometriosis [ 34]. In\nendometriotic lesions, macrophages exhibit altered pheno-\ntypes and functions, contributing not only to impaired clear-\nance of menstrual debris but also to the establishment of a\nchronic inflammatory microenvironment that supports ec-\ntopic tissue survival and immune evasion [ 34]. In this con-\ntext, macrophages are not able to manage damaged erythro-\ncytes, but contribute to ROS and cytokine production [ 35].\nThese factors activate signaling pathways, including nu-\nclear factor kappa-light-chain-enhancer of activated B cells\n(NF-κB), mitogen-activated protein kinases (MAPK), and\ncGAS–STING, which promote angiogenesis, tissue prolif-\neration, and fibrosis, all hallmarks of lesion establishment\nand progression in the context of endometriosis [ 36–38].\nIn particular, ROS activate MAPKs such as ERK, p38,\nand JNK, leading to cellular senescence, enhanced stromal\nproliferation, and inflammatory gene expression, thus con-\ntributing to lesion maintenance [ 21,39–42]. Moreover, the\nreduced expression of antioxidant enzymes, such as glu-\ntathione peroxidase (GPX), superoxide dismutase (SOD),\nand catalase (CA T), has been reported in serum and peri-\ntoneal fluid, reflecting systemic and local depletion of an-\ntioxidant defenses [ 43–46]. This imbalance results in ele-\nvated levels of oxidative byproducts such as 8-isoprostane\n(8-iso-PGF2α) and advanced oxidation of protein products,\nfurther amplifying oxidative injury [ 47]. The overall result\nis a microenvironment characterized by chronic inflamma-\ntion, oxidative stress, and immune evasion that supports the\npersistence of endometriotic implants (Table 1) [48].\nThis complex interplay underlines why oxidative\nstress and iron chelation are considered promising thera-\npeutic targets, and why agents like carnosine, with both an-\ntioxidant and metal-chelating functions, deserved detailed\nexploration in this disease context.\n3. Preclinical Insights Into the Therapeutic\nPotential of Carnosine in Endometriosis\nCarnosine is a naturally occurring dipeptide composed\nof β-alanine and L-histidine, found at high concentration\nin excitable tissues such as skeletal muscle and brain. It\nexerts multiple physiological effects, including pH buffer-\ning, antioxidant, anti-inflammatory, metal-chelating, anti-\nglycating, and immunomodulatory activities, all properties\nwhich can be useful to counteract the oxidative stress and\ninflammation characterizing endometriosis [ 49–52].\nAlthough direct studies in endometriosis models are\nnot yet published, research in non-reproductive oxidative\nstress models offers a very solid mechanistic relevance.\n3\n\nTable 1. Molecular mechanisms involved in endometriosis pathogenesis.\nPathway Component Effect\nROS and lipid peroxidation MDA, 8-iso-PGF2 α Endothelial dysfunction, pain, infertility\nIron overload Free iron, ferritin, Fenton reactions ROS production, ferroptosis\nAntioxidant depletion Thiols, GPX, SOD, catalase, total antioxidant capacity Sustained oxidative damage\nSignaling NF-κB, MAPKs, cGAS–STING Lesion growth, senescence, inflammation\nImmune dysfunction ↓ NK cytotoxicity, ↑ macrophage activation Inadequate lesion clearance\nMDA, malondialdehyde; GPX, glutathione peroxidase; SOD, superoxide dismutase; NF- κB, nuclear factor kappa-light-chain-\nenhancer of activated B cells; MAPK, mitogen-activated protein kinases; cGAS–STING, cyclic GMP-AMP synthase-stimulator\nof interferon genes; NK, natural killer.\nCarnosine has been reported to directly scavenge a vari-\nety of ROS, such as superoxide anion and hydroxyl rad-\nicals, and react with α,β-unsaturated aldehydes produced\nduring lipid peroxidation [ 50,53]. It also enhances the ac-\ntivity of endogenous antioxidant enzymes, boosting cellu-\nlar defenses [ 8]. In a zebrafish embryo model exposed\nto titanium dioxide nanoparticles, carnosine significantly\nreduced ROS production, inhibited stress marker expres-\nsion (70 kDa-HSP (Hsp70), and metallothioneins), and\nprotected against DNA and protein damage without af-\nfecting development [ 54]. Similarly, in intestinal stem\ncells challenged with mycotoxin deoxynivalenol, carno-\nsine activated the Kelch-like ECH-associated protein 1\n(Keap1)/Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)\nsignaling axis, enhancing antioxidant defenses, promoting\ncell survival, and preserving mucosal integrity [55]. Studies\non mice oral mucosa cells treated with tert-butyl hydroper-\noxide demonstrated that carnosine lowered ROS levels,\ncontrolled DNA damage (8-OH-dG, γH2A.X), downregu-\nlated senescence markers (p21 Waf1), and attenuated activa-\ntion of the Nrf2/heme oxygenase-1 (HO-1) pathway [ 56].\nFurthermore, the preservation of GPX, the key enzyme\npreventing lipid peroxidation, appears pivotal to carno-\nsine’s protective effect; in fact, in ischemia-reperfusion\nmodels, carnosine increased GPX4 expression, decreased\niron-induced lipid peroxidation, and inhibited ferroptosis\n[57]. As chelator of divalent transition metal ions, carno-\nsine binds metals like Cu 2+ and Fe 2+, preventing Fen-\nton reaction and iron-catalyzed ROS production [ 51,58].\nInflammation in endometriosis is largely driven by ROS-\nmediated activation of NF-κB pathway, leading to elevated\npro-inflammatory cytokines, angiogenesis, fibrosis, and le-\nsion growth. Carnosine has been shown to downregulate\nNF-κB signaling and to reduce pro-inflammatory media-\ntors, such as TNF- α and IL-6, across multiple cell types,\nmitigating chronic inflammation [ 59–62].\nWhile the above-mentioned models and carnosine\nmodulatory activity are not directly related to the repro-\nductive system, they illustrate carnosine’s capabilities in\nprotecting against oxidative damage in diverse cell types.\nGiven the established role of oxidative stress, mitochon-\ndrial damage, and iron-driven ROS in endometriosis, these\nmechanisms offer a strong rationale for exploring carnosine\nin both in vitro and in vivo endometriosis models.\nDespite this, some preclinical studies evaluating\ncarnosine relevance in different female reproductive con-\ntexts are available and provide encouraging insights into\nits potential for endometriosis management through reduc-\ntion of oxidative stress and inflammation. In an in vivo\nstudy conducted on female rats exposed to electromagnetic\nfield, closely related to oxidative stress development, DNA\ndamage, and deterioration of the structure and function of\nthe cells, carnosine demonstrated the ability to prevent the\nloss of primordial and primary follicles, also maintaining\nthe follicle diameter [ 63]. Additionally, carnosine supple-\nmentation during pregnancy in mice enhanced maternal and\nfetal antioxidant status, with increased SOD and GPX ac-\ntivity and reduced MDA in offsprings, indicating improved\nredox balance in reproductive tissues [ 64]. This evidence\nprovides proof of concept about carnosine potential in pre-\nserving female fertility by protecting ovarian reserve and\nenhancing antioxidant defenses under oxidative challenge\n(Fig. 3).\n3.1 Carnosine in Models of Iron-Induced Cellular Stress\nAs previously discussed, iron overload plays a pivotal\nrole in promoting oxidative stress through Fenton chem-\nistry, a process relevant to endometriosis and other chronic\ninflammatory conditions. Carnosine, due to its imida-\nzole group, exhibits significant iron-chelating properties,\nwhich contribute to its antioxidant and cytoprotective ef-\nfects. Mozdzan et al. [65] demonstrated that carnosine\neffectively chelates Fe 2+ and Cu 2+ ions and reduces hy-\ndroxyl radical generation in vitro, suggesting that its metal-\nbinding capacity could attenuate iron-driven oxidative dam-\nage. Similarly, results provided by Kang showed that\ncarnosine and its analogues (e.g., homocarnosine) prevent\nDNA damage induced by ferritin and H 2O2, further un-\nderlining a protective role against iron-mediated ROS gen-\neration [ 66]. These findings are further supported by re-\ncent in vivo studies. In a mouse model of chronic kid-\nney disease with iron overload, carnosine administration\nreduced non-heme iron accumulation in tissues and lipid\nperoxidation levels, while improving redox balance and\nhemoglobin content [67]. The authors proposed the forma-\ntion of Fe2+-GSH-carnosine ternary complexes as a mecha-\nnism of detoxification. A different study reported that oral\ncarnosine administration was able to mitigate the adverse\n4\n\n\nFig. 3. Carnosine properties in reproductive disorders. Carnosine has shown promising results in counteracting two key features of\nreproductive disorders: inflammation and oxidative stress. It scavenges ROS, prevents the oxidation of lipids, proteins, and DNA, acti-\nvates endogenous antioxidant responses via different enzymes and chelates metal ions such as Fe 2+ and Cu2+. It reduces inflammation\nby suppressing proinflammatory mediators and senescence-associated signaling through the downregulation of p21 Waf1.\ncardiac remodeling associated with diet-induced obesity in\na mouse model of enhanced lipid peroxidation (GPX4 de-\nficient mice). In this context, carnosine significantly re-\nduced iron levels and suppressed collagen-cross-linking in\nmyocardial tissue, strengthening its well-known antifibrotic\nactivity [68]. Collectively, these studies suggest that carno-\nsine may offer therapeutic benefits in disorders involving\niron overload by chelating labile iron, preventing hydroxyl\nradical formation, and activating endogenous antioxidant\npathways. This mechanism may be particularly relevant in\nendometriosis, where excess of iron and the related oxida-\ntive stress sustain lesion persistence and infertility [ 69].\n3.2 Carnosine Modulation of Macrophage Activity and\nInnate Immune Responses\nCarnosine exerts significant immunomodulatory ef-\nfects on macrophages, influencing both oxidative stress\nand inflammatory signaling [70–72]. In lipopolysaccharide\n(LPS) + interferon- γ (IFN-γ)-activated M1 macrophages,\ncarnosine treatment led to a plethora of beneficial effects\n[73]. The dipeptide was able to reduce the production of\nROS and nitric oxide (NO), downregulate the expression\nof inducible nitric oxide synthase (iNOS) and NADPH oxi-\ndases (Nox1/2), and suppress pro-inflammatory cytokines,\nwhile increasing anti-inflammatory mediators including\ninterleukin-10 (IL-10) and transforming growth factor- β1\n(TGF-β1). Moreover, carnosine treatment decreased the\nlevels of lipid peroxidation product MDA, and restored the\nexpression of antioxidant enzymes (GpX, SOD and CA T),\nwhile increasing the expressions of Nrf2 and HO-1, signif-\nicantly ameliorating the antioxidant status of the cells, and\npromoting the phenotypic switch towards the M2 state [73].\nIn a further study employing RAW 264.7 macrophages ex-\nposed to amyloid- β (Aβ) oligomers, carnosine protected\nagainst oxidative and nitrosative stress, reducing ROS, NO,\nand peroxynitrite levels, a mechanism linked to decreased\ncell death and apoptosis [ 52]. Carnosine’s ability to modu-\nlate macrophage phagocytosis and clearance functions un-\nder oxidative challenge were further demonstrated in stud-\nies showing stimulated removal of senescent fibroblasts\nand keratinocytes [ 74]. The authors stated that this ef-\nfect involves the upregulation of CD36 and the receptor\nfor advanced glycation end products (RAGE) expression,\nprobably stimulated by carnosine via the activation of the\nAKT2 signaling pathway. Although direct evidence on NK\ncell modulation is limited, it is plausible that by reduc-\ning macrophage-derived pro-inflammatory signals, carno-\nsine may indirectly influence macrophage-NK cross-talk\nand innate immune surveillance. In this context, a study\nwas conducted on mice under restraint stress, showing a\nsubsequent reduction of spleen index and number of spleen\nlymphocytes, including NK cells, whose cytotoxic activity\nwas abolished [ 75]. Still in the context of NK modulation,\noral administration of carnosine ameliorated stress-evoked\nimmunocompromise through spleen lymphocyte number\nmaintenance, thus restoring the classic activity for NK cells,\npivotal players in immune responses against pathogens and\ntumors [75]. Beyond its role in modulating macrophage ac-\ntivation and NK activity, carnosine also appears to influ-\nence adaptive immune components. In a study evaluating\nhuman peripheral blood-derived CD4 + T lymphocytes, the\ntreatment with carnosine extended their replicative lifes-\npan, while also reducing levels of oxidative DNA [ 76].\nThese findings confirm the evidence that carnosine can\nmodulate innate immune cell activity, including suppress-\ning pro-inflammatory cytokine secretion by macrophages,\n5\n\nFig. 4. The role of carnosine in immune response. Carnosine modulates macrophage activity by reducing the production of ROS, NO,\nand peroxynitrite. It attenuates inflammation by downregulating iNOS and Nox2 expression, while enhancing the anti-inflammatory\nresponse through the upregulation of IL-10, Nrf2, HO-1, CD36, RAGE, and TGF- β1. Carnosine may also support immune surveillance\nby promoting crosstalk between macrophages and NK cells. NO, nitric oxide; iNOS, inducible nitric oxide synthase; Nox2, NADPH oxi-\ndase 2; IL-10, interleukin-10; Nrf2, Nuclear factor (erythroid-derived 2)-like 2; HO-1, heme oxygenase-1; RAGE, receptor for advanced\nglycation end products; TGF- β1, transforming growth factor- β1.\nand highlight its potential to restore immune homeostasis in\ninflammatory contexts (Fig. 4).\nGiven that endometriosis is characterized by a dys-\nregulated immune response, including defective clearance\nof ectopic endometrial cells, aberrant macrophage polariza-\ntion, and impaired T cell and NK cell activity, carnosine’s\nimmunomodulatory effects may offer therapeutic benefit by\nrebalancing both innate and adaptive immune components\nwithin the peritoneal microenvironment.\n3.3 Glial Cells as Regulator of Fertility: The Role of\nCarnosine\nBeyond the well-established peripheral mechanisms,\nrecent evidence suggests that neuroinflammation and cen-\ntral nervous system regulation may also represent under-\nappreciated contributors to reproductive disorders. In the\ncontext of endometriosis, which is frequently associated\nwith central sensitization and chronic pelvic pain, explor-\ning the role of glial cells provides a novel point of view to\nunderstand how neuroimmune interactions may influence\nfertility. In particular, an alternative approach to address-\ning fertility challenges in women has been recently pro-\nposed by Desroziers [ 77], who highlighted an interesting\nand unconventional link between glial cells and PCOS. In\nher review, Desroziers [ 77] underscores how glial cells,\nincluding astrocytes and microglia, can structurally and\nfunctionally modulate neurons related to the gonadotropin-\nreleasing hormone (GnRH), allowing increased pulsatile\nor release of GnRH via morphological remodeling of glial\nprocesses. In PCOS-like animal models, abnormal neu-\nronal wiring, related to increased GABAergic synaptic in-\nputs to GnRH neurons, correlates with impaired synaptic\npruning and suggests a potential, although not yet fully elu-\ncidated, role for glial-mediated shaping of neural circuits.\nThis concept leads to a captivating hypothesis that glial\ndysfunction may contribute to neuroendocrine dysregula-\ntion in PCOS by allowing enhanced excitatory input persis-\ntence to GnRH neurons, driving LH hypersecretion and the\nresultant hormonal and ovarian symptoms [ 77,78]. Inter-\nestingly, carnosine exerts multiple modulatory effects on\nglial cells that could be linked to these mechanisms. In\na study on human HMC3 microglial cells, carnosine sig-\nnificantly reduced NO production and improved mitochon-\ndrial A TP/ADP ratio [ 79]. When the same human cells\nwere challenged with a pro-oxidative and pro-inflammatory\nstimulus represented by the combination of LPS and A TP ,\nresults obtained by HPLC analysis reported the ability of\ncarnosine to modulate ROS production and restore the\nbasal energy metabolism of the glial cells [ 80]. More-\nover, in BV-2 murine microglial cultures challenged with\nAβ, carnosine lowered reactive oxygen/nitrogen species,\nsuppressed the gene expression of iNOS, Nox1/Nox2, and\n6\n\n\nFig. 5. Proposed mechanisms linking carnosine, microglial regulation, and fertility. Carnosine is a promising regulator of fertility\ndue to its antioxidant and anti-inflammatory effects on microglia. It reduces the production of pro-inflammatory cytokines (IL-6, IL-1 β)\nand enzymes such as iNOS, while lowering NO levels. At the same time, it increases the A TP/ADP ratio, thereby enhancing cellular\nenergy status. Moreover, carnosine may help stabilize the glial microenvironment surrounding GnRH neurons, supporting hormone-\ndriven neuronal communication through the release of GnRH. IL-1 β, Interleukin-1β.\npro-inflammatory cytokines (interleukin-1 β (IL-1β), IL-6,\nIFN-γ), while rescuing IL-10 and TGF-β1 levels, highlight-\ning its anti-inflammatory and glial-regulatory actions [ 81]\n(Fig. 5).\nThe same model was also employed to assess the tran-\nscriptional regulatory activity of carnosine on glial cells\nin A β-induced stress conditions, in which the dipeptide\nwas able to upregulate the expression of CXCL2, an anti-\ninflammatory mediator, and rescue the level of markers re-\nlated to the phagocytic activity, including CD11b, CD68,\nand TNF- α. Moreover, carnosine counteracted the down-\nregulation A β-induced of CX3C motif chemokine recep-\ntor 1 (CX3CR1), the receptor for fractalkine, which is es-\nsential for neuron-microglia interactions [ 82]. Addition-\nally, further evidence emphasizes carnosine’s ability to\nmodulate microglia and astrocyte activity, to reduce ox-\nidative, nitrosative, and inflammatory stress, and to sup-\nport glial-driven metabolic cooperation with neurons [ 83].\nIn this context, a model of primary rat mixed glia cul-\ntures, composed of both microglia and astrocytes, was re-\ncently used to confirm the ability of carnosine to coun-\nteract the A β oligomers-induced oxidative stress and in-\nflammation [84]. Single-cell analyses of cellular responses\nto oligomers’ treatment revealed massive ROS and NO\nproduction and the separation of cell population in dis-\ntinct clusters, all parameters rescued and/or counteracted by\ncarnosine. By doing so, carnosine may stabilize the glial\nmicroenvironment surrounding GnRH neurons, promoting\nproper synaptic pruning, neurotransmitter regulation, and\nhormone-driven neuronal communication. This offers an\ninteresting mechanistic hypothesis: by modulating glial cell\nhealth and function, carnosine could indirectly restore phys-\niological GnRH pulsatility and ameliorate PCOS-related\nneuroendocrine disorders (Fig. 5). Given the central role of\nglial cells in neuroimmune and neuroendocrine regulation,\nthese findings, along with carnosine’s well-known neuro-\nprotective properties, may also highlight its broader rele-\nvance in neuro-rehabilitation contexts, in which restoring\nglia-mediated signaling could represent a promising thera-\npeutic target.\n3.4 Unique Features of Endometriosis and Potential\nImplications for Carnosine\nEndometriosis exhibits several disease-specific fea-\ntures that differentiate it from other chronic inflammatory\nand oxidative disorders. Lesions are strongly estrogen-\n7\n\ndependent, with aberrant hormone signaling leading to pro-\nliferation and survival of ectopic endometrial cells [ 85].\nMoreover, the progressive fibrotic remodeling of peritoneal\nlesions, mediated by excessive extracellular matrix deposi-\ntion and myofibroblast activation, represents a distinctive\nhallmark of endometriosis [86–88]. In parallel, the immune\nmicroenvironment is characterized by impaired NK cell cy-\ntotoxicity, altered macrophage polarization, and sustained\nrelease of pro-inflammatory cytokines such as TNF- α and\nIL-6, all contributing to lesion persistence and infertility\n[5,6,89–91]. Of note, chronic pelvic pain and central sensi-\ntization also highlight the contribution of neuroinflamma-\ntion and glial dysfunction to the disease pathophysiology\n[92–94].\nThese features provide a rationale to hypothesize spe-\ncific mechanisms through which carnosine might exert ben-\neficial effects in endometriosis. Beyond its antioxidant and\nmetal-chelating activities, carnosine shows antiglycating\nproperties that could attenuate fibrotic progression by lim-\niting advanced glycation end-products and tissue stiffening\n[68,95]. Its immunomodulatory action on macrophages and\ncytokine release may help restoring immune surveillance\nwithin endometriotic lesions [ 73,96]. Furthermore, evi-\ndence of carnosine’s ability to regulate glial activation and\nneuroinflammatory signaling strengthen its potential role\nin alleviating pain and neuroendocrine alterations disease-\nassociated [50,97]. Although direct studies in endometrio-\nsis are lacking, these unique disease-specific aspects point\nto potential multimodal mechanisms through which carno-\nsine may act, encouraging further research.\n4. Antioxidant and Cytoprotective Actions of\nCarnosine in Male Reproductive Health\nWhile the focus has been on female reproductive dis-\norders so far, it is important to underline that oxidative\nstress, immune dysregulation, and metabolic imbalance\nare also major features of male infertility. These shared\npathogenic pathways suggest that carnosine’s antioxidant\nand cytoprotective effects may extend beyond female con-\ntexts, providing benefits in male reproductive health as\nwell. In particular, male infertility is classically related\nto oxidative insults to spermatozoa, leading to decreased\nmotility, DNA fragmentation, and mitochondrial dysfunc-\ntion [ 98]. In different preclinical models of reproductive\ntoxicity in male animals, carnosine demonstrated protective\neffects via antioxidant and anti-glycating pathways. For in-\nstance, in male rats treated with cyclophosphamide hydrox-\nydaunomycin, oncovin, and prednisone (CHOP), a combi-\nnation of chemotherapeutics commonly used to induce go-\nnadotoxicity in experimental models, carnosine supplemen-\ntation preserved testicular function, reduced lipid peroxida-\ntion, and decreased oxidative DNA damage [ 99]. Carno-\nsine was also tested in a different model of testicular tox-\nicity induced by sodium valproate, in which the dipep-\ntide, along with Coenzyme Q10 co-administration, was\nable to increase the levels of reproductive hormones such\nas testosterone, FSH, and LH in serum, thereby increas-\ning the levels of biochemical parameters such as SOD,\nGPX, and catalase [ 100]. Additionally, carnosine was\nshown to mitigate testicular aging induced by galactose\nexposure through its anti-glycating and ROS-scavenging\nproperties [ 101]. Further support for carnosine’s cytopro-\ntective role in the male reproductive system derive from a\nmodel of malnutrition-induced hypogonadism, where rats\nfed with a protein-deficient diet exhibited severe reductions\nin testicular weight, sperm count and viability, along with\nhormonal imbalances and increased pro-inflammatory and\napoptotic markers in testicular tissue [ 102]. Carnosine ad-\nministration reversed these alterations by restoring antioxi-\ndant defenses and anti-inflammatory activity. Similarly, in\na model of lead (Pb)-induced reproductive toxicity, char-\nacterized by increased oxidative stress, mitochondrial dys-\nfunction, and poor sperm parameters, carnosine supplemen-\ntation alleviated these alterations, confirming its protective\nrole for mitochondria and redox homeostasis [103]. Beyond\nanimal models, carnosine has also demonstrated promis-\ning results in human sperm manipulation contexts. When\nadded during semen processing, carnosine improved mi-\ntochondrial activity and beat-cross frequency (BCF), sup-\nporting its potential in assisted reproduction technologies\n[104]. These beneficial mitochondrial effects were repro-\nposed and assessed in studies on quail sperms, where carno-\nsine, present in seminal plasma, improved different motil-\nity parameters after in vitro storage, suggesting an innova-\ntive and critical function of imidazole dipeptides in sperm\npreservation [105]. This function appears significantly rel-\nevant in semen cryopreservation, where oxidative stress is\na critical factor. In stallion semen, higher carnosine lev-\nels were associated with better tolerance to cooling and\nfreezing, and with reduced MDA levels, proving that carno-\nsine was effective in removing lipid peroxidation products.\nThese findings suggest that carnosine may act as a nat-\nural buffer against cryo-induced oxidative insults, poten-\ntially enhancing sperm resistance during biotechnological\nprocesses [ 106]. This evidence confirms that carnosine\nsupports male reproductive health by attenuating oxidative\ndamage, preserving mitochondrial integrity, and sustaining\nhormonal and spermatogenic homeostasis under stress con-\nditions (Fig. 6).\nAlthough endometriosis represents a different disease\nrelated to women, the oxidative and immune pathways im-\nplicated in its pathogenesis show a notable overlap with\nthose involved in male infertility. This overlap suggests\nthat carnosine, due to its broad-spectrum cytoprotective ac-\ntions, could be considered as a supportive intervention in\nboth contexts.\n5. Clinical Trial With Carnosine Involving\nEndometriosis-Related Markers\nTo date, no clinical trial has specifically evaluated\ncarnosine supplementation in women with endometriosis.\nHowever, human studies in related inflammatory and ox-\n8\n\n\nFig. 6. Role of carnosine in male reproductive health. Carnosine has shown protective activity towards male reproductive health,\ndecreasing DNA damage and glycation, along with oxidative stress and the related peroxidation of lipids. Overall, it also allows an\nimprovement of redox homeostasis.\nidative contexts provide translational insights. A meta-\nanalysis of randomized controlled trials involving histidine-\ncontaining dipeptides (including carnosine) reported signif-\nicant reductions in systemic oxidative markers (e.g., MDA\nand 8-OHdG) and inflammatory markers (e.g., C-reactive\nprotein (CRP) and TNF- α), along with the increase in an-\ntioxidant defense parameters (e.g., CA T and SOD) [ 107].\nIn metabolic syndrome patients, carnosine combined with\nvitamin B complex significantly decreased immune acti-\nvation markers such as neopterin, a pyrazine-pyrimidine\nmolecule that monocytes and macrophages create in re-\nsponse to IFN-γ released by activated T-cells, also improv-\ning oxidative stress profiles [108]. These trials demonstrate\nthat carnosine can reduce key inflammatory and oxidative\nmarkers implicated in endometriosis. Basing on these find-\nings, it is possible to hypothesize the rationale for a pilot\nclinical trial of carnosine in endometriosis, beginning with\noxidative/inflammatory biomarker endpoints and proceed-\ning towards clinical outcomes such as pain relief and lesion\nsize reduction.\n6. Conclusions, Current Limitations, and\nFuture Perspectives\nThere are numerous evidence showing that the natural\ndipeptide carnosine possesses a therapeutic potential in the\ncontext of human reproduction. It has shown to exert its\nantioxidant and potential protective effects on sperm and\nreproductive tissues. Additionally, carnosine has shown to\nplay a role in several aspects of female reproduction, includ-\ning ovarian health, fetal development, and potentially in-\nfluencing pregnancy outcomes. In particular, studies have\nshown the ability of carnosine to protect ovarian follicles\nfrom damage caused by electromagnetic fields, potentially\nimproving fertility. Furthermore, maternal supplementa-\ntion with carnosine has shown promise in enhancing fetal\ngrowth and development in animal models. In addition to\nthe above direct positive modulatory effects, carnosine has\nshown to be able to modulate endometriosis-related mark-\ners as well as macrophages and microglia, the latter emerg-\ning as an innovative regulator of female fertility, and in par-\nticular in the context of endometriosis.\nIn summary, carnosine has shown very promising re-\nsults in supporting reproductive health, but further research\nis needed to fully understand its therapeutic potential on re-\nproductive disorders, also strengthening the possible bene-\nfits of carnosine administration for prevention and/or treat-\nment of endometriosis. In this context, a critical limi-\ntation of the current literature is represented by the ab-\nsence of direct in vitro and in vivo studies using estab-\nlished endometriosis models (e.g., rodent models of en-\ndometriosis, human endometriotic stromal cell cultures),\nalong with the lack of clinical studies focused on the role of\ncarnosine in the management of endometriosis markers and\nsymptoms. Carnosine’s multimodal potential including an-\ntioxidant, chelating, and immunomodulatory properties is\ndeeply reported in the literature, and systematic reviews of\nclinical studies on the role of oxidative stress and the po-\ntential of antioxidant therapy in endometriosis identify sev-\neral candidates that have been tested, but reports on carno-\n9\n\nsine are still missing [ 109–111]. Given the absence of di-\nrect carnosine-endometriosis studies, in the present review\nwe chose to focus on mechanistic and preclinical evidence\nregarding the multimodal potential of this dipeptide, and\non well-established pathogenic pathways in endometriosis\n(iron overload, ROS, immune dysfunction) to justify the\nconsideration of carnosine as a possible therapeutic candi-\ndate. This approach is intentionally hypothesis-generating:\nthe conclusions drawn here are provisional and aim to moti-\nvate dedicated new in vitro, in vivo, and early clinical stud-\nies. Future research must prioritize investigating the effects\nof carnosine in this specific disease to validate the promis-\ning mechanisms proposed herein as well as to determine\noptimal dosing and delivery strategies.\nAbbreviations\n8-isoPGF2α, 8-isoprostane; 8-OHdG, 8-\nhydroxydeoxyguanosine; A β, Amyloid- β; BCF, Beat-\ncross frequency; CA T, Catalase; CHOP , Cyclophos-\nphamide, hydroxydaunomycin, oncovin, and prednisone;\ncGAS–STING, Cyclic GMP-AMP synthase-stimulator\nof interferon genes; CRP , C-reactive protein; GnRH,\nGonadotropin-releasing hormone; GPX, Glutathione\nperoxidase; HO-1, Heme oxygenase-1; Hsp70, 70 kDa-\nHSP; IFN- γ, Interferon- γ; IL-1 β, Interleukin-1 β; IL-6,\nInterleukin-6; IL-10, Interleukin-10; iNOS, Inducible\nnitric oxide synthase; Keap1, Kelch-like ECH-associated\nprotein 1; LPS, Lipopolysaccharide; MDA, Malondialde-\nhyde; MAPK, Mitogen-activated protein kinases; NF- κB,\nNuclear factor kappa-light-chain-enhancer of activated B\ncells; NKG2D, NK group 2D; NK, Natural killer; Nox1/2,\nNADPH oxidases; Nrf2, Nuclear factor (erythroid-derived\n2)-like 2; PCOS, Polycystic ovary syndrome; RAGE,\nReceptor for advanced glycation end products; ROS,\nReactive oxygen species; SOD, Superoxide dismutase;\nTGF-β1, Transforming growth factor- β1; TNF- α, Tumor\nnecrosis factor-α.\nAuthor Contributions\nProject administration and conceptualization of the\nmanuscript: GCaro and GCaru; literature search: GCaro,\nLDP , KP , SAB, VC, AG, RM, GiuL, BT, VDP , EM, FB,\nAMA, GiaL, and GCaru; writing—original draft: GCaro\nand GCaru; preparation of the figures: GCaro, LDP , and\nGCaru; writing—review & editing: GCaro, LDP , KP , SAB,\nVC, AG, RM, GiuL, BT, VDP , EM, FB, AMA, GiaL,\nGCaru. All authors contributed to editorial changes in\nthe manuscript. All authors read and approved the final\nmanuscript. All authors have participated sufficiently in\nthe work and agreed to be accountable for all aspects of the\nwork.\nEthics Approval and Consent to Participate\nNot applicable.\nAcknowledgment\nNot applicable.\nFunding\nThis work was supported by the Italian Ministry of\nHealth (Ricerca Corrente) and partially supported by PRIN\n2022 grant “Counteracting Human Infertility Pathophysiol-\nogy (CHIP)”, number 2022KREEEF- University of Cata-\nnia.\nConflict of Interest\nThe authors declare no conflict of interest. In partic-\nular, the judgments in data interpretation and writing were\nnot influenced by the relationship between Prof. Giuseppe\nLazzarino and LTA-Biotech srl.\nReferences\n[1] Scutiero G, Iannone P , Bernardi G, Bonaccorsi G, Spadaro S,\nV olta CA,et al. Oxidative Stress and Endometriosis: A System-\natic Review of the Literature. 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