Mechanisms and clinical implications of oxidative stress-mediated endometrial receptivity impairment in polycystic ovary syndrome.

Gut microbiota dysbiosis is emerging as a critical upstream regulator in PCOS, indirectly driving the endometrial oxidative-inflammatory network, while the role of the endometrial microbiota itself requires focused attention. Gut microbiota dysbiosis may influence endometrial immune homeostasis in PCOS through microbiota–immune interactions that promote chronic low-grade inflammation. While evidence linking gut dysbiosis to systemic metabolic-inflammatory disturbances in PCOS is growing [ 52 ], direct evidence regarding the role of the endometrial microbiota in this disorder remains extremely limited and inconsistent. Most research focuses on intestinal communities [ 53 , 54 ]. The few studies that have directly sampled the endometrial microbiota in PCOS are constrained by several critical methodological flaws: small, heterogeneous sample sizes, high risk of contamination from the lower reproductive tract, and significant methodological variability in sterile sampling techniques and sequencing platforms. These limitations severely complicate the interpretation and generalization of findings, mandating a highly cautious approach when evaluating the direct contribution of endometrial microbes to PCOS pathophysiology. The healthy gut microbiome maintains systemic homeostasis by regulating bile acid and short-chain fatty acid (SCFA) metabolism, with SCFAs acting as key anti-inflammatory agents [ 55 – 57 ]. Gut dysbiosis compromises the intestinal barrier, leading to increased translocation of bacterial products like LPS [ 58 ]. This triggers low-grade systemic inflammation and OS, which subsequently affects distal organs [ 58 ]. In PCOS, characteristic gut dysbiosis leads to amplified systemic oxidative and inflammatory signaling that indirectly reaches the endometrium [ 59 ]. Systemic evidence shows that elevated circulating LPS stimulates TLR4 on immune and endothelial cells [ 58 , 60 ]. While direct experimental evidence in PCOS endometrial cells is lacking, it is speculated that these heightened systemic inflammatory mediators and endotoxins may activate TLR4 on endometrial cells, triggering the NF-κB pathway and local inflammation [ 59 ]. Such disruptions in the endometrial microenvironment may potentially impair the immune tolerance required for successful implantation [ 59 , 61 ]. While gut dysbiosis may act as a potential upstream inflammatory contributor, the established metabolic and endocrine hallmarks of PCOS—IR and Hyperandrogenism—constitute powerful downstream drivers [ 4 , 62 ]. These factors do not act in isolation; rather, they synergize with microbial-driven low-grade inflammation and OS, compounding the endometrial redox imbalance and magnifying the defect in receptivity [ 15 , 33 ]. Beyond acting as a parallel pathological feature, gut microbiota dysbiosis may represent a common upstream factor that integrates metabolic, oxidative, and inflammatory disturbances in PCOS. The following sections discuss how microbiota-associated alterations in redox balance, metabolic signaling, and immune regulation may collectively contribute to impaired endometrial receptivity. Alterations in gut microbiota composition have been implicated in metabolic dysfunction and insulin resistance in PCOS, which in turn may adversely affect endometrial receptivity [ 63 ]. Metabolic dysfunction, primarily driven by IR in PCOS, is a key upstream factor contributing to systemic OS, which subsequently impairs local endometrial function [ 38 , 46 ]. In the general population, IR and MetS induce hyperlipidemia and hyperglycemia. This state increases circulating free fatty acids and disrupts glucose metabolism, leading to mitochondrial electron transport chain stress and the overproduction of ROS [ 64 , 65 ]. These systemic redox changes collectively exert negative effects on endometrial cellular energy metabolism and function by altering substrate availability [ 11 , 65 , 66 ]. In women with PCOS, this systemic IR translates directly into endometrial cellular impairment. Several studies on PCOS endometrial biopsies and primary cells have demonstrated a significant downregulation of the insulin-sensitive PI3K/Akt signaling pathway and reduced expression of the glucose transporter GLUT4 [ 47 , 67 , 68 ]. Hyperandrogenism, a defining feature of PCOS, does not solely impact ovarian function but directly exerts detrimental, pro-oxidative effects on the endometrium, severely compromising receptivity. While androgen excess is primarily associated with reproductive pathology, physiological levels of androgens are essential for normal endometrial proliferation and differentiation through receptor-mediated mechanisms [ 31 , 32 ]. However, supraphysiological androgen levels can lead to adverse effects, including altered expression of local growth factors and inflammatory mediators in endometrial cells, disrupting the delicate hormonal milieu required for implantation [ 51 , 69 ]. In PCOS, the sustained elevated androgen levels exacerbate OS in the endometrial microenvironment, potentially via upregulation of ROS-generating enzymes such as NADPH oxidases (NOXs). However, the functional consequence of this upregulation may be context-dependent; for instance, in vascular endothelial cells, NOX4-derived ROS have been shown to counteract testosterone-induced dysfunction rather than exacerbate it [ 70 ]. Given the lack of direct PCOS endometrial cell data, it is hypothesized that this mechanism amplifies the local oxidative burden, compounding the anti-estrogenic and pro-inflammatory effects of HA [ 9 , 71 ]. While gut dysbiosis, IR, and HA originate from distinct physiological systems, they converge on a common final pathway: the generation of excessive ROS that overwhelms endometrial defense [ 50 , 72 ]. Dysbiosis provides the inflammatory trigger (LPS) [ 73 ], metabolic dysfunction provides the substrate overload (glucose/FFAs), and HA compromises the antioxidant shield. Together, they sustain the mitochondrial dysfunction and NF-κB activation ultimately locking the endometrium in a non-receptive state [ 49 , 74 ]. This tripartite model underscores that isolated interventions are likely insufficient [ 75 ]. A combinatorial therapeutic strategy is rational: probiotics/prebiotics to quench the inflammatory ignition [ 76 ], insulin sensitizers to limit the metabolic fuel [ 74 ], and ferroptosis inhibitors [ 77 ] or SHBG modulators to repair the breached antioxidant shield. By simultaneously targeting multiple nodes of this network, it may be possible to sustainably break the vicious cycle and restore endometrial redox homeostasis. This concept is supported by preclinical studies in related gynecological conditions demonstrating that multi-modal interventions—such as dietary modulation of inflammation and the microbiome [ 78 ], or combined anti-inflammatory compounds targeting NF-κB and MAPK pathways [ 79 ]—can effectively disrupt pathological feedback loops. Although these findings do not directly address PCOS or redox homeostasis, they provide a proof-of-concept for the potential of network-targeted strategies in female reproductive disorders (Fig. 3 ). Fig. 3 Comparative Pathophysiological Mechanisms of PCOS and Endometriosis. This figure illustrates the pathophysiological mechanisms of PCOS and endometriosis. PCOS is associated with alterations in gut microbiota, OS, and activation of inflammatory pathways, leading to metabolic disturbances and reproductive dysfunction. In contrast, endometriosis is linked to immune and metabolic dysregulation, characterized by increased IR, androgen excess, and impaired follicular development. The diagram highlights the interplay among inflammation, OS, immune activation, and metabolic disorders in both conditions and their collective impact on reproductive health Comparative Pathophysiological Mechanisms of PCOS and Endometriosis. This figure illustrates the pathophysiological mechanisms of PCOS and endometriosis. PCOS is associated with alterations in gut microbiota, OS, and activation of inflammatory pathways, leading to metabolic disturbances and reproductive dysfunction. In contrast, endometriosis is linked to immune and metabolic dysregulation, characterized by increased IR, androgen excess, and impaired follicular development. The diagram highlights the interplay among inflammation, OS, immune activation, and metabolic disorders in both conditions and their collective impact on reproductive health

This narrative review synthesizes current evidence on OS, metabolic dysfunction, and endometrial impairment in PCOS. A structured literature search was conducted in PubMed, Web of Science, and Google Scholar for studies published from January 2000 to November 2025. Google Scholar was used only as a supplementary source to capture studies not indexed in PubMed or Web of Science.Search terms included: “Polycystic Ovary Syndrome/PCOS”, “Endometrial Receptivity/Decidualization/Implantation Failure”, “Oxidative Stress/Reactive Oxygen Species”, “Insulin Resistance/Metabolic Syndrome”, and “Gut Microbiota”. Eligible studies were English-language original research articles, reviews, or meta-analyses involving human PCOS populations or relevant cellular/animal models with mechanistic relevance. Case reports, letters, and purely epidemiological studies were excluded. The search yielded several hundred records, from which approximately 150 articles were selected for detailed review. As is appropriate for narrative reviews, no formal risk-of-bias assessment or meta-analysis was performed. However, the strength and limitations of the available evidence (e.g., cross-sectional vs. mechanistic studies, sample sizes) were critically appraised within the mechanistic sections to assist interpretation.

In conclusion, this review synthesizes current evidence suggesting that impaired endometrial receptivity in PCOS arises from complex interactions among oxidative stress, metabolic dysregulation, and inflammatory activation. Importantly, emerging data indicate that microbiota alterations may function as an integrative upstream regulator linking these interconnected pathways. Through its potential effects on metabolic homeostasis, immune modulation, and redox balance, microbiota dysbiosis may contribute to the endometrial microenvironmental disturbances observed in PCOS. However, this conceptual framework remains hypothesis-generating and underscores the need for further mechanistic and clinical studies to clarify causality and tissue-specific effects. Future research must prioritize the translation of this framework into clinical practice. This requires: standardized characterization of the endometrial microbiome and redox landscape in PCOS; mechanistic validation using advanced models like endometrial organoids; and biomarker-stratified clinical trials that test the efficacy of rationally designed combination therapies (e.g., probiotics with insulin sensitizers or ferroptosis inhibitors) against objective ER and pregnancy outcomes.

Several limitations of this review should be acknowledged. First, although a substantial body of evidence supports the association between oxidative stress, metabolic dysfunction, and impaired endometrial receptivity in PCOS, most available data are derived from observational clinical studies, animal models, or in vitro experiments. These study designs inherently limit causal inference, particularly with respect to human endometrial physiology during the implantation window. Second, direct mechanistic evidence obtained from human endometrial tissues or primary endometrial cells in women with PCOS remains limited. Many proposed pathways linking oxidative stress to decidualization failure, mitochondrial dysfunction, and inflammatory activation are extrapolated from non-endometrial models or inferred from systemic metabolic data, which may not fully capture tissue-specific regulatory mechanisms. Third, while emerging studies suggest a potential role of gut microbiota dysbiosis in PCOS-related reproductive dysfunction, direct evidence linking gut or endometrial microbiota alterations to impaired endometrial receptivity is still scarce. Existing studies are often constrained by small sample sizes, cross-sectional designs, and methodological challenges, including potential contamination during endometrial microbiome sampling and heterogeneity in sequencing approaches. Finally, the therapeutic implications discussed in this review—such as microbiota-targeted interventions, antioxidant strategies, and combined metabolic–endocrine modulation—are largely hypothesis-generating. Robust clinical trials with well-defined endometrial receptivity endpoints and pregnancy outcomes are required before these approaches can be translated into routine clinical practice.

MetS, HA, and gut microbiota dysbiosis are not isolated features of PCOS but interconnected components of a multidirectional regulatory network. Their interactions amplify OS, chronic inflammation, and metabolic dysfunction, ultimately impairing ER. Understanding these cross-system relationships is essential to elucidate the integrated pathogenesis of PCOS (Fig.  4 ). Fig. 4 Metabolic and Hormonal Interplay in PCOS Pathogenesis. This diagram outlines the multifactorial mechanisms underlying PCOS, integrating hormonal dysregulation and metabolic dysfunction. Elevated anti-Müllerian hormone (AMH) stimulates theca cell androgen production, while increased LH and unaltered/low FSH disrupt ovarian follicular development. Concurrently, hepatic fat accumulation and elevated VLDL levels exacerbate liver IR, impairing basal insulin secretion and postprandial glucose regulation. Pancreatic islet triglyceride accumulation further compromises insulin response. These metabolic disturbances, combined with HA and IR, contribute to reduced ER, highlighting the systemic interplay between reproductive endocrine abnormalities and metabolic dysregulation in PCOS Metabolic and Hormonal Interplay in PCOS Pathogenesis. This diagram outlines the multifactorial mechanisms underlying PCOS, integrating hormonal dysregulation and metabolic dysfunction. Elevated anti-Müllerian hormone (AMH) stimulates theca cell androgen production, while increased LH and unaltered/low FSH disrupt ovarian follicular development. Concurrently, hepatic fat accumulation and elevated VLDL levels exacerbate liver IR, impairing basal insulin secretion and postprandial glucose regulation. Pancreatic islet triglyceride accumulation further compromises insulin response. These metabolic disturbances, combined with HA and IR, contribute to reduced ER, highlighting the systemic interplay between reproductive endocrine abnormalities and metabolic dysregulation in PCOS IR and HA reinforce each other through a well-established feedback loop [ 69 , 80 ]. Hyperinsulinemia enhances ovarian theca cell androgen production and increases free IGF-1 activity, while elevated androgens exacerbate visceral adiposity and impair insulin signaling in metabolic tissues [ 81 , 82 ]. This “insulin–androgen axis” accelerates lipid accumulation [ 83 ], which may increase FFA release, and enhances ROS generation through mitochondrial overload. Moreover, IR reduces antioxidant enzyme activity and promotes NF-κB activation, creating a pro-inflammatory systemic environment that further stimulates androgen synthesis [ 80 , 84 ]. Androgens significantly influence gut microbial composition. HA has been shown to reduce α-diversity and enrich LPS-producing Gram-negative bacteria, thereby increasing endotoxin leakage and systemic inflammation [ 85 , 86 ]. Conversely, dysbiosis impairs bile acid metabolism and SCFA production, which can modify steroid hormone synthesis and receptor expression [ 59 , 87 ]. This bidirectional interaction creates a “microbiota–steroid axis,” where HA alters microbial ecology, and microbial metabolites in turn modulate androgen activity and inflammatory signaling [ 88 , 89 ]. Both pathways converge on ROS overproduction and contribute to endometrial oxidative dysregulation. Metabolic disturbances are closely tied to gut microbiota alterations. Obesity and IR are associated with reduced levels of beneficial SCFA-producing bacteria and increased intestinal permeability [ 90 ]. The resulting endotoxemia activates TLR4/NF-κB pathways, exacerbating IR and promoting the release of pro-inflammatory cytokines [ 91 ]. Simultaneously, dysbiosis-associated increases in BCAAs impair glucose metabolism and mitochondrial function, further intensifying OS [ 92 ]. These changes create a cycle in which metabolic stress worsens dysbiosis, and dysbiosis reinforces metabolic dysfunction, each amplifying oxidative imbalance.

Polycystic ovary syndrome (PCOS) is a common reproductive–metabolic disorder characterized by ovulatory dysfunction, hyperandrogenemia (HA), insulin resistance (IR), and diverse metabolic abnormalities [ 1 ]. Affecting approximately 5–15% of women of reproductive age worldwide, PCOS is a leading cause of anovulatory infertility [ 2 ]. Although ovulation induction therapies can restore ovulation in most patients, pregnancy and live-birth rates remain significantly lower than expected, indicating that ovulation alone does not fully account for impaired fertility in PCOS [ 3 , 4 ]. Increasing evidence suggests that endometrial receptivity (ER), rather than oocyte quality, may represent the critical limiting factor, particularly in women who exhibit normal embryo development yet experience implantation failure [ 5 , 6 ]. PCOS is a heterogeneous condition with distinct endocrine, inflammatory, and metabolic phenotypes. Obese and lean PCOS patients show different patterns of IR, lipid abnormalities, chronic inflammation, and redox imbalance, while the Rotterdam subtypes also exhibit divergent pathophysiological features [ 7 ]. These phenotypic differences imply that ER impairment in PCOS is not driven by a single mechanism but results from the convergence of multiple systemic disturbances [ 8 ]. Notably, current clinical guidelines do not recommend using PCOS phenotypes as a mandatory step in routine clinical decision-making, as subtype identification is not required for determining general management strategies [ 2 ]. Among these, oxidative stress (OS)---defined as an imbalance between reactive oxygen species (ROS) generation and antioxidant capacity—has emerged as a central mediator linking metabolic dysregulation with disrupted endometrial function. Physiologically, ROS participate in cyclic endometrial remodeling, hormone signal transduction, decidualization, and embryo implantation [ 1 , 9 ]. However, excessive ROS accumulation disrupts mitochondrial activity, activates NF-κB–mediated inflammation, damages DNA and cellular structures, and suppresses implantation-related molecules such as integrins, leukemia inhibitory factor (LIF), and HOXA10 [ 6 , 10 , 11 ]. Clinical studies consistently report elevated OS biomarkers (e.g., MDA, 8-OHdG) and reduced antioxidant enzyme activity in women with PCOS, correlating with poor ER and increased miscarriage risk [ 5 , 9 , 12 ]. Yet, the causal pathways linking systemic metabolic dysfunction to local endometrial oxidative imbalance remain insufficiently clarified. In addition to HA and IR, emerging evidence highlights the role of metabolic syndrome (MetS) and gut microbiota dysbiosis as critical upstream contributors to ROS overproduction [ 13 ]. These intersecting mechanisms suggest that PCOS-related ER impairment arises from a broader metabolic–inflammatory–endocrine–microecological network rather than isolated defects [ 9 , 14 ]. While the individual impacts of HA, IR, and OS on PCOS are well-documented, most existing reviews treat these factors as parallel or isolated mechanisms [ 15 ]. Furthermore, the link between gut microbiota dysbiosis and ER is often discussed only as a correlation, lacking a unified mechanistic framework that explains how systemic dysbiosis drives local endometrial pathology. While traditional models often address hyperandrogenism and IR as primary, parallel drivers of PCOS pathology, they frequently fail to account for the rising evidence of systemic low-grade inflammation and immune dysregulation in the syndrome, particularly the pervasive role of the gut-metabolic axis [ 2 , 16 , 17 ]. Furthermore, existing theories often treat these factors as equal contributors without proposing a hierarchical regulatory structure or identifying a potential upstream initiator [ 18 ]. To address this gap and integrate the multi-systemic nature of PCOS pathogenesis with the specific impairment of ER, we propose a novel, integrated Microbiota-first Hierarchical Framework. This framework hypothesizes that gut dysbiosis may contribute to a cascade of systemic metabolic and endocrine disturbances through inflammatory and OS pathways, suggesting a possible sequential, rather than strictly parallel, pathological order that culminates in ER failure [ 17 ]. To bridge these gaps, this review distinguishes itself from prior literature in three key aspects: Firstly, we propose an integrated “Gut-Metabolism-Endocrine” network model, uniquely positioning gut microbiota dysbiosis as a potential upstream regulator that initiates the systemic OS cascade, rather than merely a secondary symptom. Secondly, unlike reviews focusing solely on ovulation, we specifically elucidate how these systemic metabolic–microbial disturbances converge to disrupt the endometrial window of implantation via specific oxidative pathways (e.g., mitochondrial dysfunction and ferroptosis). Thirdly, we synthesize the “metabolism–inflammation–endocrine–microbiota” interaction to offer new insights into multi-target therapies, suggesting that restoring gut homeostasis may be a critical strategy for improving endometrial quality. This review aims to summarize current evidence on the mechanisms by which oxidative stress and metabolic abnormalities are associated with impaired endometrial receptivity in PCOS, with a particular focus on the emerging role of microbiota as an integrative upstream regulator linking metabolic dysfunction, inflammatory activation, and endometrial impairment.

Traditionally, research on infertility has often focused on unilateral defects in either oocyte/embryo quality or ER. However, successful implantation relies on finely tuned bidirectional signaling between the embryo and the endometrium [ 19 , 20 ]. The quality of the oocyte/embryo not only determines its own developmental potential but also dynamically modulates endometrial immune tolerance, gene expression, and transient receptivity through paracrine signals such as cytokines, exosomes, and metabolites secreted by the embryo [ 20 ]. Conversely, the endometrial microenvironment (e.g., redox status, inflammatory levels) profoundly influences the developmental trajectory and post-implantation fate of the embryo [ 19 ]. In the context of PCOS, this bidirectional dialogue may be abnormally amplified [ 21 ]. On one hand, PCOS-associated oocyte metabolic phenotypic abnormalities may lead to an imbalance in embryo-derived signals, thereby exacerbating endometrial inflammation and OS. On the other hand, the inherent OS and chronic inflammatory microenvironment of the PCOS endometrium may further distort the reception and response to signals from the embryo, creating a vicious cycle that collectively reduces implantation rates [ 21 ]. Therefore, future research requires the adoption of embryo-endometrium co-study models (such as embryo-endometrial co-culture systems, analysis of gene expression in recipient endometrium, and donor oocyte transplantation control studies) to dissect this complex causal chain, thereby providing a more comprehensive understanding of implantation failure mechanisms in PCOS.

Accumulating evidence suggests that gut microbiota dysbiosis in PCOS may contribute to endometrial oxidative stress by promoting systemic metabolic inflammation and disrupting redox homeostasis. ER refers to the transient state in which the endometrium becomes capable of supporting embryo adhesion, invasion, and early development [ 22 , 23 ]. This “window of implantation” typically occurring 5–7 days after ovulation, relies on coordinated regulation of hormone signaling, integrin expression, cytokine activity, stromal decidualization, and angiogenesis [ 24 , 25 ]. Impairment in any of these processes may lead to implantation failure or early pregnancy loss [ 26 ]. Clinical evidence indicates that ER defects account for nearly two-thirds of recurrent implantation failure cases, highlighting their critical role in reproductive success [ 27 ]. Importantly, pregnancy outcomes in recipients receiving oocytes from women with PCOS are comparable to those from healthy donors, suggesting that endometrial dysfunction—rather than oocyte competency—is a major contributor to infertility in PCOS. In women without PCOS, tightly regulated reactive oxygen species (ROS) generation is an integral component of normal endometrial physiology. Physiological ROS levels participate in cyclic endometrial remodeling, hormone signal transduction, stromal decidualization, and embryo–maternal communication during the window of implantation. This redox balance is maintained by robust antioxidant systems, ensuring that ROS function primarily as signaling molecules rather than sources of cellular damage. Disruption of this finely controlled redox homeostasis—rather than ROS presence per se—marks the transition from physiological regulation to pathological impairment. OS arises when the production of ROS surpasses antioxidant defenses [ 28 , 29 ]. Under physiological conditions, ROS act as signaling molecules that are essential for proper endometrial decidualization [ 30 ]. In addition, ROS have been implicated in cyclic endometrial remodeling [ 22 , 23 ], modulation of estrogen and progesterone responses [ 31 , 32 ], and immune cell recruitment during the window of implantation [ 25 , 33 ]. Antioxidant systems—including enzymatic defenses such as SOD, CAT, and GPX, and non-enzymatic factors such as vitamins C and E—maintain redox balance and support normal mitochondrial function [ 28 , 34 , 35 ] (Fig. 1 ). Fig. 1 Mechanisms of Oxidative Stress Generation and Its Interaction with the Antioxidant Defense System. The left side lists the body's antioxidant systems, including enzymatic antioxidants (such as SOD, CAT, GSH-Px) and non-enzymatic antioxidants (vitamins C/E, glutathione, minerals, etc. ), which neutralize ROS and mark the main types of ROS. The right side elaborates on the pathological effects of OS: it induces cell damage through mechanisms such as ion channel opening, lipid peroxidation, protein modification, and DNA oxidation Mechanisms of Oxidative Stress Generation and Its Interaction with the Antioxidant Defense System. The left side lists the body's antioxidant systems, including enzymatic antioxidants (such as SOD, CAT, GSH-Px) and non-enzymatic antioxidants (vitamins C/E, glutathione, minerals, etc. ), which neutralize ROS and mark the main types of ROS. The right side elaborates on the pathological effects of OS: it induces cell damage through mechanisms such as ion channel opening, lipid peroxidation, protein modification, and DNA oxidation Numerous clinical studies have documented elevated levels of oxidative biomarkers—such as malondialdehyde (MDA), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and increased TOS/TAC ratios—in the serum, follicular fluid, and endometrial tissue of women with PCOS [ 10 , 36 , 37 ]. More specifically, at the cellular level, Zeng et al. provided evidence of oxidative damage in the endometrium of women with PCOS, as shown by changes in antioxidant enzyme expression, SIRT3 localization, and mitochondrial function [ 10 ]. Abnormal mitochondrial DNA copy number and mitochondrial gene mutations in patients with PCOS have been the focus of recent research, with mitochondrial dysfunction increasingly recognized as a contributing factor in PCOS [ 38 ]. These genetic defects were accompanied by significantly reduced mitochondrial membrane potential (MMP) and elevated intracellular ROS levels in PCOS-derived ESCs compared to controls [ 10 ], confirming that systemic OS translates directly into organelle dysfunction within the endometrial compartment [ 39 ]. Animal experiments provide additional mechanistic insights. Models of OS induction demonstrate ovarian and uterine abnormalities, including ovarian morphological changes [ 40 , 41 ] as well as uterine architectural disturbances and impaired endometrial epithelial cell proliferation [ 42 ]. Antioxidant interventions such as astaxanthin have been shown to restore redox balance in the follicular microenvironment and improve oocyte/embryo quality in PCOS patients [ 43 ]. However, direct evidence for similar protective effects within the endometrium remains limited. These findings from ovarian studies reinforce the role of oxidative imbalance in disrupting reproductive function, though species differences and supra-physiological dosages limit generalization to clinical settings. While the association between systemic and local OS is robust, studies directly detecting and proving the mechanisms of ROS/OS action solely within endometrial tissues or primary/cell line endometrial cells (endometrial stromal cells and endometrial epithelial cells) remain limited [ 11 , 44 ]. ER critically depends on the transformation of endometrial stromal cells (ESCs) into decidual cells, a process known as decidualization [ 45 ]. This transformation is highly energy-demanding and relies heavily on optimal mitochondrial function [ 46 ]. In PCOS, elevated OS within endometrial tissue exerts specific detrimental effects on ESC mitochondria, promoting the opening of the mitochondrial permeability transition pore (mPTP) [ 46 ]. This event disrupts the mitochondrial respiratory chain and leads to a marked reduction in intracellular adenosine triphosphate (ATP) production [ 28 , 46 ]. Because decidualization requires substantial metabolic support for its morphological and biochemical transitions [ 46 , 47 ]. The disruption of mitochondrial energy metabolism—leading to ATP depletion—may compromise the decidual response. Consistently, reduced endometrial ATP production has been observed in patients with repeated implantation failure (RIF) [ 48 ], a condition associated with impaired decidualization. As an intracellular second messenger, OS serves as a major trigger of chronic inflammation. Systemic drivers of OS—such as lipopolysaccharide (LPS)—activate the NF-κB signaling pathway within both endometrial epithelial cells and stromal cells [ 49 ]. Sustained activation of this pathway leads to increased production of pro-inflammatory cytokines, including IL-6 and TNF-α, in the endometrial microenvironment [ 9 , 33 ]. These cytokines disrupt the immune-tolerant state required during the implantation window, shifting it toward an immune-rejection phenotype and ultimately impeding embryo adhesion and invasion [ 33 , 50 ]. Elevated OS directly interferes with the transcription and expression of endometrium-specific genes that define the implantation window, resulting in the downregulation of receptivity-related molecules in both the epithelial and stromal compartments [ 11 , 44 ]. HOXA10 is a pivotal transcription factor determining ER. OS specifically reduces HOXA 10 transcriptional activity in stromal cells, likely through mechanisms involving histone modifications or direct disruption of regulatory signaling pathways [ 11 , 51 ]. The decline in HOXA10 expression subsequently decreases its downstream targets—such as integrin αVβ3—within the endometrium, thereby contributing to impaired adhesive capacity in PCOS [ 11 , 51 ]. These alterations compromise the molecular machinery necessary for successful embryo implantation. Collectively, OS may function as an important mediator contributing to endometrial dysfunction in PCOS. By impairing decidualization, disrupting immune tolerance, and suppressing receptivity-related molecular expression, OS plays a central role in the deterioration of ER (Fig.  2 ). Fig. 2 Core Pathophysiological Network of PCOS. This schematic diagram depicts the interconnected mechanisms underlying PCOS-associated endometrial dysfunction. Central neuroendocrine dysregulation drives ovarian dysfunction and hyperandrogenism (HA), which in turn promote a chronic inflammatory state characterized by elevated ROS, oxidative stress (OS), and cytokine imbalance (e.g., increased IL-6, dysregulated IL-10). This pro-inflammatory milieu, coupled with aberrant SHBG/GPX4 regulation, activates the ferroptosis pathway and establishes a vicious cycle with insulin resistance (IR). The convergence of these pathological processes ultimately leads to endometrial damage and implantation failure. Arrows indicate cascade effects and interactions among components Core Pathophysiological Network of PCOS. This schematic diagram depicts the interconnected mechanisms underlying PCOS-associated endometrial dysfunction. Central neuroendocrine dysregulation drives ovarian dysfunction and hyperandrogenism (HA), which in turn promote a chronic inflammatory state characterized by elevated ROS, oxidative stress (OS), and cytokine imbalance (e.g., increased IL-6, dysregulated IL-10). This pro-inflammatory milieu, coupled with aberrant SHBG/GPX4 regulation, activates the ferroptosis pathway and establishes a vicious cycle with insulin resistance (IR). The convergence of these pathological processes ultimately leads to endometrial damage and implantation failure. Arrows indicate cascade effects and interactions among components