The Role of STING ‐Mediated Activation of the Integrated Stress Response in Inflammation‐Induced Depletion of Ovarian Reserve

ABSTRACT Inflammatory responses within the ovarian microenvironment are increasingly recognized as significant disruptors of ovarian function, yet their specific effects on early follicular development, particularly the activation of primordial follicles, remain poorly understood. In this study, we employ a mouse model of transient lipopolysaccharide (LPS)‐induced inflammation to mimic the inflammatory conditions associated with chronic pelvic inflammatory disease (PID) and systemic infections. We demonstrate that LPS stimulation triggers the premature activation of primordial follicles, leading to a depletion of the ovarian reserve. This finding underscores the detrimental impact of inflammation on ovarian health. However, we also identify a protective mechanism mediated by the cGAS‐STING pathway, a central regulator of innate immunity and cellular stress responses. Activation of the cGAS‐STING pathway effectively inhibits LPS‐induced primordial follicle activation, thereby preserving ovarian function. Further mechanistic investigations reveal that the Integrated Stress Response (ISR), a downstream effector of STING signaling, plays a critical role in this protective process. The ISR, orchestrated by kinases such as PERK, modulates cellular homeostasis under stress conditions by phosphorylating eukaryotic initiation factor 2α (eIF2α). Our data show that STING activation induces ISR signaling, which in turn suppresses the overactivation of primordial follicles. To explore the therapeutic potential of this pathway, we utilized STING and ISR agonists, which successfully mitigated LPS‐induced primordial follicle activation and preserved ovarian reserve in our experimental model. These findings highlight the dual role of inflammation in ovarian biology: while acute inflammatory stimuli can disrupt follicular quiescence, the cGAS‐STING‐ISR axis serves as a critical regulatory network to counteract these adverse effects. Our study not only elucidates the molecular mechanisms underlying inflammation‐induced ovarian dysfunction but also identifies STING and ISR as promising therapeutic targets for preserving ovarian reserve in women exposed to chronic inflammatory conditions. These insights have significant clinical implications, offering potential strategies to protect ovarian function in patients with inflammatory diseases or those undergoing treatments that compromise ovarian health.