The inflammatory clock: how cGAS-STING ticks in the aging ovary

Nuclear DNA damage and the subsequent leakage of genetic material into the cytosol are considered a critical initiating events in cellular senescence and tissue aging. Genotoxic insults from chemotherapy, environmental toxins, or the natural aging process induce DNA double-strand breaks, genomic instability, and telomere shortening across multiple ovarian cell types, including granulosa cells, oocytes, and stromal cells, with oocytes and granulosa cells being particularly vulnerable because of their limited DNA repair capacity and high metabolic demand. Importantly, the age-associated accumulation of DNA damage in granulosa cells may reflect both a consequence of aging-related decline in repair mechanisms and a driving force that promotes further cellular senescence and ovarian functional decline. In oocytes, this vulnerability is further compounded by their reliance on long-term DNA damage tolerance rather than continuous cell cycle–coupled repair, a feature that distinguishes germ cells from proliferating somatic cells and predispose them to persistent cytosolic DNA signaling when repair capacity is exceeded (Stringer et al., 2020).

Such damage can lead to the formation of cytoplasmic chromatin fragments (CCFs), which serve as potent ligands for cGAS recognition and pathway activation (Dou et al., 2017; Shen et al., 2021). Mechanistic insights into CCF-mediated cGAS activation are primarily derived from studies in senescent fibroblasts and tumor cells, while direct experimental validation in ovarian cells remains limited. Nevertheless, emerging observations in aging ovarian tissues suggest that analogous processes may occur under conditions of sustained genomic stress., and it is plausible that age-dependent cytosolic DNA accumulation in granulosa cells could engage cGAS–STING signaling, amplifying downstream NF-κB and IRF3 responses. Recent studies indicate that the integrity of the nuclear envelope is a key regulator of this process; for example, downregulation of the nuclear lamina protein Lamin B1 has been shown in non-ovarian models to accelerates nuclear envelope rupture and CCF formation. Concurrently, impaired degradation of cytosolic DNA, such as through deficient TREX1 enzyme activity, results in persistent cGAS stimulation (Frediani et al., 2022; Mohr et al., 2021).

Upon binding to cytosolic DNA, cGAS catalyzes the synthesis of 2′3′-cGAMP, which activates STING and downstream NF-κB and IRF3 signaling axes. NF-κB activation induce the expression of pro-inflammatory cytokines (e.g., IL-6, TNF-α) and can also influence genomic stability by modulating the activity of DNA repair factors, such as those involved in homologous recombination (Xu et al., 2024). Within the ovarian context, NF-κB functions not only as an amplifier of DNA damage–induced stress signaling but also indirectly affects oocyte maturation and follicular microenvironment homeostasis through the regulation of pro-inflammatory and pro-fibrotic factors (Sze et al., 2022; García-García et al., 2021). The link between DNA damage and NF-κB activation is particularly evident in granulosa cells. Studies comparing granulosa cells from young and aged mice have revealed an age-dependent increase in the DNA damage marker γH2AX, which correlates with enhanced NF-κB nuclear localization, suggesting that DNA double-strand breaks are potent activators of NF-κB signaling in these cells (Zhang et al., 2015). This age-dependent DNA damage may both result from diminished DNA repair capacity during aging and act as a driver of granulosa cell senescence, potentially through activation of the cGAS–STING pathway. Supporting this notion, in vitro experiments demonstrate that inhibition of NF-κB transcriptional activity attenuate DNA damage–induced expression of pro-inflammatory cytokines and partially rescue cell proliferation, positioning NF-κB as a critical signal amplifier in granulosa cell senescence. Furthermore, in models of age-related ovarian fibrosis, aberrant NF-κB activation in stromal cells is associated with the accumulation of pro-fibrotic factors such as TGF-β1, and inhibition of NF-κB alleviates this fibrotic response (Grzeczka et al., 2025). This cascade can be further exacerbated by the activation of PARP1 in response to DNA damage, which depletes intracellular NAD⁺ pools and promotes cellular senescence, thereby forming a reinforcing loop with NF-κB signaling and senescence-associated secretory phenotype (SASP) factors (Salminen et al., 2012).

In parallel, STING activation recruits TBK1 to phosphorylate IRF3, initiating the transcription of type I interferons (IFN-α/β) and interferon-stimulated genes (ISGs) (Yu and Liu, 2024). In the early stages of DNA damage, this interferon response may exert context-dependent protective effects, including enhancement of cellular defense mechanisms and maintenance of mitochondrial homeostasis (Li and Chen, 2018). However, under conditions of chronic or irreparable genomic damage, persistent IRF3/type I interferon signaling is hypothesized to disrupt ovarian cellular homeostasis, thereby accelerating follicle depletion and oocyte quality decline (Titus et al., 2013; Yu et al., 2015; Mao et al., 2024), Clinical observations of elevated DNA damage markers, inflammatory cytokines, and type I interferon signatures in aged ovaries are consistent with the potential involvement of the cGAS–STING–NF-κB/IRF3 axis in human ovarian aging, although direct causal evidence in ovarian cells is still limited (Al Hamrashdi and Brady, 2022; Cao, 2022; Mao et al., 2024).

In summary, nuclear DNA damage in the ovary initiates a deleterious signaling cascade—DNA damage/CCF formation/cGAS–STING activation/NF-κB and type I interferon signaling/SASP secretion—ultimately driving cellular senescence and functional decline. The type I interferon response thus represents a double-edged sword, and the threshold at which its role shifts from protective to pathological remains a critical area for future investigation.

Mitochondria play a central role in ovarian aging, functioning both as the primary source of reactive oxygen species (ROS) and as a highly vulnerable target of age-related damage (Yan et al., 2022). ROS—including superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (·OH)—can exert context-dependent effects: under physiological conditions, they participate in essential signaling and cellular defense, whereas persistent or excessive ROS accumulation, resulting from overproduction or impaired clearance, induces oxidative stress and damages proteins, lipids, and nucleic acids (Zhao et al., 2019). Within mitochondria, ROS are inevitable byproducts of oxidative phosphorylation, and the integrity of the mitochondrial membrane is therefore critical for maintaining redox homeostasis, particularly in metabolically active ovarian cells (Zhao et al., 2019; Tirichen et al., 2021).

A variety of stressors, including chemotherapeutic agents such as Triptolide (TPL) and endocrine disturbances like hyperandrogenism, can compromise mitochondrial membrane integrity in ovarian cells. Although mechanistic insights into mitochondrial membrane disruption and mtDNA release were initially derived from non-ovarian models, based on studies in other senescent or somatic cells, it is plausible that similar processes occur in aging ovarian cells. Disruption of mitochondrial membranes may facilitate the leakage of mitochondrial DNA (mtDNA) into the cytosol, where it is recognized by cGAS and triggers activation of the cGAS–STING pathway (McArthur et al., 2018; Cheng et al., 2025). Subsequent activation of this pathway amplifies inflammatory signaling through NF-κB and IRF3, leading to increased expression of pro-inflammatory cytokines and interferon-stimulated genes (ISGs). Under conditions of sustained activation, these inflammatory mediators not only exacerbate local inflammation but also impair mitochondrial respiratory chain function, potentially further enhancing ROS production (Rongvaux et al., 2014). In addition, NF-κB can modulate the transcription of mitochondrial enzymes and antioxidant systems, thereby contributing to ROS accumulation (Nisr et al., 2019), while IRF3/type I interferon signaling may indirectly increase ROS levels by altering mitochondrial membrane potential and bioenergetic balance (Nanayakkara et al., 2019; Abad et al., 2024).

Together, these events establish a self-reinforcing loop in which elevated ROS further damages mitochondrial membranes, promotes additional mtDNA leakage, and induces secondary nuclear DNA damage, leading to the formation of micronuclei or cytoplasmic chromatin fragments (CCFs) (Xi et al., 2025). In aged granulosa cells, these increases in ROS and DNA damage may reflect both a consequence of age-associated decline in repair and antioxidant defenses and a driver that accelerates cellular senescence and functional deterioration.These cytosolic nucleic acids could perpetuate cGAS–STING activation and sustain inflammatory signaling, which, although direct evidence in naturally aged granulosa cells is limited, is supported by experimental models in which mtDNA leakage activates cGAS–STING and amplifies NF-κB/IRF3 signaling, reinforcing oxidative stress and inflammatory pathways (Hong et al., 2024; Mittal et al., 2014).

The impact of this ROS–mtDNA–cGAS–STING loop varies among ovarian cell types, reflecting their distinct metabolic demands and stress sensitivities. Granulosa cells appear particularly vulnerable to ROS accumulation, rapidly exhibiting mitochondrial dysfunction, functional decline, and senescent phenotypes (Wen et al., 2024; Zhao et al., 2025). Oocytes are highly sensitive to both oxidative stress and inflammatory cytokines, which impair meiotic maturation and developmental competence (Tariq et al., 2025). Stromal cells can further amplify local damage through paracrine inflammatory signaling, thereby contributing to progressive deterioration of the follicular microenvironment (Rowley et al., 2020).

Preclinical studies provide supporting evidence for this model. In mouse ovaries exposed to TPL or hyperandrogenism, mtDNA leakage is markedly increased and accompanied by heightened activation of the cGAS–STING–NF-κB/IRF3 axis, elevated inflammatory markers, increased ROS levels, and compromised follicle quality (Cheng et al., 2025; Cai et al., 2025). In vitro studies further demonstrate that inhibiting mtDNA release or pharmacologically blocking STING signaling attenuates ROS accumulation, alleviates inflammation, and delays follicular apoptosis (Zhao et al., 2024). Recent work has identified additional molecular components that are likely involved in this network, including the NLRP3 inflammasome, mitochondrial channel proteins such as VDAC1, and antioxidant enzymes (e.g., SOD2 and GPX4), collectively forming a complex regulatory circuit that promotes ovarian aging (Navarro-Pando et al., 2021; Hu et al., 2025; Yan et al., 2022). Clinically, elevated levels of cell-free mitochondrial DNA (cf-mtDNA) detected in ovarian tissue and follicular fluid from POI patients likely reflect sustained mitochondrial distress and chronic innate immune activation, although direct evidence linking these mechanisms to cGAS–STING activation in human ovarian cells remains limited (Zhou et al., 2023).

In summary, ROS appear to function as both signaling mediators and drivers of damage in ovarian aging. Chronic activation of the ROS–mtDNA–cGAS–STING–inflammation feedback loop, initiated by mitochondrial dysfunction, may accelerate granulosa cell and oocyte decline, remodels the ovarian microenvironment, and ultimately contributes to depletion of the follicle reserve. While this pathway offers promising therapeutic targets for POI, its redundant and self-amplifying nature suggests that multi-node or combinatorial interventions may be required to effectively mitigate ovarian functional decline.

Chronic low-grade inflammation is widely recognized as a hallmark pathological feature of ovarian aging. With progressive decline in ovarian tissue function, persistent activation of the DNA damage response (DDR) occurs, accompanied by sustained secretion of pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as chemokines including CCL2/MCP-1 and CXCL8/IL-8. Together, these factors could establish a state of chronic inflammatory signaling within the local ovarian microenvironment (Shen et al., 2023; Zhu et al., 2025). Although typically mild in magnitude, this inflammation may accumulate over time, potentially disrupting cellular homeostasis, promoting immune cell recruitment, and facilitating stromal remodeling and fibrosis. Increasing evidence suggests that chronic low-grade inflammation not only reflects functional dysregulation of senescent cells but also provides a permissive foundation for the development and maintenance of the senescence-associated secretory phenotype (SASP) (Hense et al., 2024; Pan et al., 2025).

SASP constitutes a central molecular node linking cellular senescence to persistent inflammation. It encompasses a broad spectrum of bioactive factors secreted by senescent cells, including canonical pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), extracellular matrix-remodeling enzymes (MMP-3, MMP-9), pro-fibrotic mediators (transforming growth factor-β, TGF-β), and immune-modulatory molecules. Through autocrine and paracrine actions, these components propagate inflammatory signaling, amplify tissue damage, and induce secondary senescence in neighboring cells (Zhu et al., 2021; Yue et al., 2022; Ye et al., 2024). Within ovarian tissue, granulosa cells appear to represent a major source of SASP, while stromal and infiltrating immune cells may respond to SASP cues, collectively forming a multicellular inflammation–senescence network that reinforces ovarian dysfunction (Yan et al., 2024; Zhao et al., 2020). Importantly, genotoxic stress and inflammatory signaling are not restricted to granulosa cells. Theca cells, stromal fibroblasts, endothelial cells, and infiltrating immune cells within the ovary are likewise exposed to oxidative and inflammatory insults, and based on studies in other senescent or somatic cells, it is plausible that they contribute to cGAS–STING activation and SASP propagation, thereby reinforcing tissue-wide inflammatory and fibrotic remodeling (Zhu et al., 2025; Isola et al., 2024).

Mechanistically, SASP production is governed by multiple interconnected signaling pathways. The NLRP3 inflammasome acts as a sensor in many cell types of intracellular danger signals, including cytosolic DNA fragments and extracellular ATP, leading to caspase-1 activation and subsequent maturation and release of IL-1β and IL-18, thereby potentially generating a potent pro-inflammatory amplification loop (Kelley et al., 2019; Fujimura et al., 2023). In parallel, opening of mitochondrial membrane channels such as voltage-dependent anion channel 1 (VDAC1) facilitates mitochondrial DNA (mtDNA) leakage into the cytosol, which can activate both inflammasome signaling and the cGAS–STING pathway (Kim et al., 2019). Sustained activation of downstream transcriptional programs, particularly NF-κB and p38 MAPK signaling, appears to drive high-level expression of SASP-associated genes, including IL-6, CXCL8, MMP-3, MMP-9, and TGF-β, thereby maintaining senescent cells in a chronic secretory state (Kim et al., 2019; Niklander et al., 2021). In addition, DDR signaling contributes to SASP induction via the ATM–NF-κB axis, while epigenetic and metabolic regulators such as BRD4 and mTORC1 support the long-term stability of SASP gene expression (Zhao et al., 2020; Herranz and Gil, 2018). In the context of ovarian aging, these pathways establish a self-perpetuating inflammatory–senescence environment characterized by chronic inflammation, SASP production, and cellular damage. While this environment may create conditions under which cytosolic DNA accumulates and cGAS–STING could be engaged, it remains unclear whether SASP itself directly triggers cGAS–STING activation in ovarian cells. Consistent with this model, animal studies and in vitro analyses using PCOS or follicular fluid–based systems suggest that cGAS–STING activation is associated with granulosa cell inflammation and apoptosis, whereas pharmacological or genetic inhibition of this pathway may attenuate inflammatory signaling and delays follicular dysfunction (Zhao et al., 2024; Ye et al., 2024). Additionally, cGAS–STING activation can influence the ovarian immune landscape by promoting recruitment of innate immune cells and shaping local inflammatory responses, further contributing to tissue senescence.

Beyond its effects on individual cells, SASP may exert broad paracrine influences that remodel the ovarian microenvironment, including alterations in vascular structure, extracellular matrix composition, and local immune status. These changes accelerate follicular aging, reduce the pool of developmentally competent follicles, and ultimately contribute to ovarian functional decline and the onset of POI (Hense et al., 2024; Yue et al., 2022; Isola et al., 2024). Collectively, these findings position SASP as a pivotal driver of ovarian aging through its ability to sustain and amplify chronic inflammation within a multicellular and multifactorial network. Nevertheless, most current evidence derives from in vitro–based models or short-term animal studies. The spatiotemporal dynamics of SASP secretion in vivo, as well as its precise impact across different stages of follicular development, remain incompletely understood and warrant further investigation using advanced tools such as SASP-reporter mouse models.

During ovarian aging, disruption of the balance between apoptosis and autophagy functions as a key mechanism driving follicular depletion and functional decline. Autophagy is a fundamental cellular homeostatic process responsible for the degradation of damaged mitochondria, misfolded protein complexes, and cytosolic DNA, thereby potentially preserving intracellular integrity and stress tolerance (Li et al., 2020). Under physiological conditions, granulosa cells and oocytes maintain moderate basal autophagy, which effectively clears stress-induced damage, limits accumulation of danger-associated molecular patterns, and supports follicle survival and maturation. However, with advancing age or exposure to metabolic or genotoxic stress, autophagic capacity in ovarian cells declines progressively, leading to the accumulation of damaged organelles, cytosolic DNA, and stress signals, thereby shifting the cellular fate toward apoptosis and establishing a maladaptive autophagy–apoptosis imbalance (Li et al., 2024; Cai et al., 2024; Dong et al., 2022).

Emerging evidence specifically in ovarian cells indicates that cGAS–STING signaling is engaged when cytosolic DNA accumulates due to impaired autophagy. For instance, granulosa cell–specific stress models, such as Immp2l deficiency, demonstrate that mitochondrial and cytosolic DNA accumulation activates cGAS–STING, triggers downstream NF-κB and interferon-stimulated gene expression, and promotes senescence and apoptosis; pharmacological inhibition of STING mitigates these effects (Pan et al., 2025). Similarly, in PCOS mouse models, hyperandrogenism-induced stress activates cGAS–STING–NF-κB signaling in granulosa cells, while STING inhibition reduces inflammatory cytokine expression and apoptosis, supporting a modulatory role of this pathway in ovarian cell stress responses (Cai et al., 2025; Zhao et al., 2024).

Mechanistically, in ovarian cells, reduced autophagic flux prevents efficient clearance of cytosolic DNA fragments, which then accumulate and engage cGAS, activating STING. Activated STING subsequently enhances NF-κB and p38 MAPK pathways, promoting the transcription of pro-inflammatory cytokines and apoptosis-related genes, intensifying Bax induction and Caspase-3 activation, and thereby accelerating apoptotic cell death (Li et al., 2022). Evidence in ovarian cells also suggests that cGAS–STING may participate in feedback regulation of autophagy, potentially engaging Beclin-1–dependent pathways, although the exact mechanisms in oocytes and granulosa cells remain to be fully elucidated (Gui et al., 2019; Lu et al., 2023).

Under conditions of sustained stress or age-associated autophagy impairment, persistent STING activation in ovarian cells can reinforce apoptotic and pro-inflammatory signaling. Preclinical studies using ovarian cell–specific models show that pharmacological inhibition of STING or enhancement of autophagy reduces cytosolic DNA accumulation, attenuates Caspase-3 activation, and mitigates apoptosis, supporting a modulatory role of cGAS–STING in the autophagy–apoptosis axis.

Collectively, these observations suggest that autophagy imbalance functions not only as an upstream trigger of apoptosis but also interacts with cGAS–STING signaling specifically in ovarian cells to amplify stress and senescence signals. Rather than acting in isolation, apoptosis and autophagy are tightly interconnected under complex regulatory networks, with cGAS–STING representing an influential, yet ovarian cell–specific, modulator. Future studies using ovarian cell–specific genetic models (e.g., granulosa-specific or oocyte-specific cGAS/STING knockout) are required to definitively establish the causal role of this pathway in age-related autophagy–apoptosis imbalance.

Telomere shortening is a hallmark of cellular senescence, and telomere dysfunction can activate the DNA damage response (DDR), thereby serving as an initiating signal for cellular functional decline (Abdisalaam et al., 2020). Accumulating evidence suggests that telomere attrition may directly engage the cGAS–STING pathway through cytosolic DNA leakage, linking genomic instability to innate immune activation (Şerifoğlu et al., 2025). In a telomerase-deficient (tert^−/−) zebrafish model, despite pronounced telomere shortening, genetic ablation of STING restored cellular proliferative capacity, reduced p53 expression, and decreased DNA damage markers such as γH2AX. These findings indicate that cGAS–STING functions as a critical signal amplifier in telomere dysfunction–induced senescence. Mechanistically, telomere attrition promotes the formation of micronuclei or chromosomal fragments that leak into the cytosol, where they are sensed by cGAS, leading to STING activation and induction of type I interferons and pro-inflammatory cytokines. This process establishes a chronic low-grade inflammatory milieu that accelerates tissue aging.

This mechanism has also been observed in human tissues (Şerifoğlu et al., 2025). For example, alveolar type II epithelial (ATII) cells from aged donors exhibit telomere shortening accompanied by accumulation of cytosolic double-stranded DNA and activation of the cGAS–STING pathway, as evidenced by IRF3 upregulation and increased pro-inflammatory cytokine expression. Together, these observations support the concept that telomere dysfunction promotes DNA leakage and cGAS–STING activation, thereby amplifying aging-associated inflammatory signals in experimental systems and correlating with chronic inflammation and cellular dysfunction in clinical contexts. These findings raise the possibility that telomere–cGAS–STING signaling may represent a potential intervention axis to delay ovarian aging (Ebata et al., 2022), although direct evidence in ovarian tissue remains limited.

Beyond telomere attrition, cells undergoing prolonged replication or entering senescence frequently exhibit extensive chromatin remodeling, altered histone modifications, and aberrant DNA methylation patterns. Such epigenetic alterations can substantially reshape the transcriptional programs governing DNA repair, cell cycle control, and immune responses (Joshi et al., 2017). Notably, in cGAS-deficient mouse embryonic fibroblasts (MEFs), telomere shortening and cell cycle arrest still occur; however, p21 protein expression and senescence-associated β-galactosidase positivity are reduced. These findings suggest that cGAS may not only function as a cytosolic DNA sensor but may also modulate the execution or reinforcement of telomere-driven senescence programs (Yang et al., 2017a).

In parallel, epigenetic regulators can directly influence DNA sensing capacity. For instance, the arginine methyltransferase PRMT5 methylates the DNA sensor IFI16, reducing its affinity for double-stranded DNA and thereby suppressing downstream activation of the cGAS–STING–TBK1–IRF3 signaling cascade. This modulation ultimately attenuates type I interferon production and pro-inflammatory cytokine expression (Kim et al., 2020; Dai et al., 2022). Collectively, these findings outline a mechanistic continuum in which epigenetic dysregulation alters DNA sensing thresholds, facilitating cGAS–STING activation and promoting cellular senescence.

Although direct experimental validation of these mechanisms in ovarian cells is still scarce, they have been consistently demonstrated across multiple in vitro systems and somatic tissue models. Given that granulosa cells, oocytes, and supporting ovarian somatic cells are exposed to prolonged replicative stress, oxidative damage, and age-associated epigenetic drift, telomere dysfunction and epigenetic aberrations are likely to intersect with cGAS–STING signaling during ovarian aging. Nevertheless, extrapolation from somatic cell models to the ovarian context—particularly to oocytes, which are terminally differentiated and non-renewable—requires caution. The unique telomere maintenance strategies and epigenetic landscape of oocytes may confer distinct regulatory features to cGAS–STING signaling that remain to be elucidated.

The cGAS–STING pathway plays a pivotal role in ovarian aging and POI progression. Direct inhibition of this pathway has attracted considerable attention as a potential therapeutic strategy. Multiple small-molecule inhibitors targeting either cGAS or STING block inflammatory signaling and reduce ovarian cell senescence in preclinical models.

Activation of cGAS requires binding to cytosolic DNA, after which cGAS catalyzes the synthesis of the cyclic dinucleotide 2′3′-cGAMP, triggering downstream STING-mediated inflammatory responses. Consequently, inhibitors targeting cGAS generally operate via two mechanisms: blocking cGAS–DNA binding, or suppressing its catalytic activity, thereby reducing cGAMP production at the initiation stage of the pathway and attenuating type I interferon and pro-inflammatory cytokine release. Among these, RU.521 was the first structurally characterized small molecule to competitively bind cGAS, preventing DNA entry into the catalytic pocket and significantly reducing type I interferon levels in mouse models (Vincent et al., 2017). Subsequent compounds, TDI-6570 and PF-06928215, exhibit improved selectivity for the cGAS catalytic site, enhancing inhibition of cGAMP generation in both in vitro and in vivo inflammation models (Mankan et al., 2014; Cornelis et al., 2020). G150 has demonstrated reversible inhibition of both human and murine cGAS, providing a platform for cross-species studies (Lama et al., 2019). Inhibitors that disrupt cGAS–DNA condensate formation target the emerging mechanism of phase separation with high specificity. However, their efficacy and safety in ovarian aging models remain largely unexplored, and cell-specific delivery represents a major translational challenge.

STING, as the direct receptor of cGAMP, undergoes multi-step activation involving ligand binding, dimerization, and palmitoylation. STING inhibitors block downstream inflammatory signaling by interfering with these regulatory steps. For example, H-151 covalently modifies key residues of STING, preventing its translocation and inhibiting IRF3 phosphorylation, thereby mitigating systemic inflammation (Haag et al., 2018). C-176/C-178 act via an allosteric mechanism to prevent STING dimerization and show effective anti-inflammatory activity in autoimmune models (Mukai et al., 2016); SN-011 occupies the ligand-binding site of STING, demonstrating pronounced anti-inflammatory effects in preclinical models (Li et al., 2025), and the natural cyclic peptide Astin C inhibits the STING–TBK1 interaction, reducing IRF3 activation and inflammatory signaling (Li et al., 2018).

Although these small molecules have shown promising results in inflammation and aging models, their application in human ovarian aging and POI remains at an early exploratory stage. A critical limitation is that the cGAS–STING pathway also plays essential roles in antitumor immunity, and long-term systemic inhibition may carry potential risks, such as increased tumor susceptibility, which must be rigorously evaluated in future clinical translation efforts.

Mitochondrial dysfunction and oxidative stress are considered core drivers of ovarian aging. Declines in mitochondrial membrane potential, excessive ROS production, and mtDNA leakage not only directly damage granulosa and oocyte cells, but also activate the cGAS–STING pathway, inducing chronic inflammation and senescence-associated secretory phenotype (SASP). To target these pathological events, a series of upstream protective strategies have been developed, including mitochondria-targeted antioxidants, broad-spectrum antioxidants, and DNA repair enhancers, which can maintain cellular homeostasis and reduce ROS and mtDNA leakage, thereby indirectly suppressing aberrant cGAS–STING activation.

Mitochondria-targeted coenzyme Q10 (Mitoquinone, MitoQ) selectively accumulates within mitochondria to scavenge ROS, significantly restoring membrane potential and improving oocyte maturation and follicle viability (Wang et al., 2023). The mitochondrial protective peptide SS-31 (Elamipretide) stabilizes membrane potential and optimizes mitochondrial energy metabolism, enhancing mitochondrial homeostasis and developmental competence in thawed ovarian tissue and in vitro cultured oocytes (Yao et al., 2024). Coenzyme Q10 (CoQ10) improves electron transport chain efficiency, reducing ROS generation and ameliorating oocyte mitochondrial function, demonstrating anti-aging effects in animal studies and assisted reproduction clinical trials (Ben-Meir et al., 2015). Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) not only enhance mitochondrial metabolism but also improve follicle reserve and oocyte quality via sirtuin (SIRT)-mediated autophagy and DNA repair pathways (Liang et al., 2020); Spermidine promotes mitophagy to maintain cellular homeostasis, further improving oocyte function (Zhang et al., 2023). Collectively, restoring mitochondrial homeostasis not only optimizes ovarian bioenergetics but also reduces ROS and mtDNA leakage, providing a theoretical basis for indirect inhibition of cGAS–STING signaling.

N-acetylcysteine (NAC) enhances glutathione levels to lower ROS and protect granulosa and oocyte cells (Yang et al., 2017b). Resveratrol (RSV) activates SIRT1/3 pathways to improve mitochondrial function, reduce oxidative stress, and has been shown to enhance oocyte quality and follicle viability in mice and assisted reproduction populations (Okamoto et al., 2022). Melatonin (MT), as an endogenous antioxidant, directly scavenges free radicals and stabilizes mitochondrial membrane potential, improving oocyte quality and reducing ovarian oxidative stress in both animal experiments and human ART trials (Tamura et al., 2020). Other antioxidants, including Taurine, Epigallocatechin gallate (EGCG), Theaflavin (TF), and Vitamins E/C, also reduce ROS, alleviate DNA damage, and indirectly suppress cGAS–STING activation through anti-inflammatory effects (Shang et al., 2024). These agents can act synergistically with mitochondrial homeostasis modulators, collectively mitigating oxidative stress and inflammatory burden to delay ovarian aging.

NMN and NR increase intracellular NAD⁺ levels, activating DNA repair pathways including poly ADP-ribose polymerase (PARP) and SIRT1/6, thereby reducing double-strand breaks and cytosolic DNA accumulation and attenuating cGAS–STING activation (Huang et al., 2022). Resveratrol similarly promotes DNA repair via SIRT1 signaling, delaying cellular senescence (Wang et al., 2022). EGCG and Riboflavin (Vitamin B₂) have been shown in basic studies to enhance DNA repair capacity and reduce ROS-induced DNA breaks (Tobi et al., 2002; Dricot et al., 2024). Although data in ovarian models are limited, small-molecule modulators of ATM and ATR kinases, established regulators of DNA damage response, have demonstrated potential for broader applications in DNA repair and warrant exploration in ovarian aging studies (Weber and Ryan, 2015).

Together, mitochondrial homeostasis modulators, antioxidants, and DNA repair enhancers form a multilayered intervention network, from upstream control of ROS and energy metabolism to DNA damage repair. This network not only improves ovarian cell function but also indirectly prevents excessive cGAS–STING activation, offering a pharmacological framework for delaying ovarian aging and premature ovarian insufficiency.

Given that ovarian aging is driven by upstream mitochondrial dysfunction, oxidative stress, and DNA damage, together with downstream overactivation of cGAS–STING signaling, combinatorial strategies targeting both upstream and downstream nodes may provide more effective protection than single-target interventions. For example, enhancing DNA repair capacity may reduce cytosolic DNA accumulation, while pharmacological inhibition of STING can directly suppress downstream inflammatory signaling, thereby alleviating chronic inflammation and the SASP phenotype from multiple levels.

Beyond direct inhibition, emerging studies in other disease contexts suggest that qualitative modulation of cGAS–STING downstream signaling outputs could provide a more refined therapeutic concept. In oncology models, persistent STING activation has been shown in certain settings to promote an immunosuppressive microenvironment; notably, co-administration of a TLR2 agonist was reported to “reprogram” STING downstream signaling by enhancing NF-κB activity while attenuating IRF3-dependent interferon responses, thereby overcoming therapeutic resistance (Song et al., 2025). Importantly, these observations are derived exclusively from tumor systems and should be regarded as a forward-looking hypothesis when extrapolated to ovarian biology, as direct experimental evidence supporting such signaling modulation in ovarian tissue is currently lacking. Moreover, the ovarian system—particularly the presence of non-renewable oocytes with highly specialized genomic and mitochondrial regulation—introduces unique biological risks and constraints, raising the possibility that interference with innate immune signaling outputs may have unintended consequences distinct from those observed in proliferative tumor cells. Nevertheless, despite these limitations, this oncology-informed framework provides a conceptual basis for cautiously exploring whether selective downstream signaling modulation, rather than global pathway inhibition, could theoretically attenuate chronic inflammation while permitting adaptive tissue responses in ovarian aging models.

At present, robust clinical efficacy data directly targeting the cGAS–STING pathway in premature ovarian insufficiency are lacking. Most available evidence is derived from mechanistically informed preclinical studies or indirect clinical observations. Across diverse ovarian injury and aging models, interventions that attenuate aberrant cGAS–STING activation—either through direct pathway inhibition or upstream preservation of mitochondrial and genomic integrity—have been associated with functional improvements, supporting a mechanism–function alignment and suggesting translational relevance, even though definitive therapeutic efficacy in humans remains to be established.

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