SIRT5–RAC2 Axis Drives Monocyte‐to‐Macrophage Differentiation to Promote Inflammatory Injury in Premature Ovarian Insufficiency

Premature ovarian insufficiency (POI) is a major cause of infertility and endocrine dysfunction, in which chronic inflammation plays a critical role. The homeostasis of tissue-resident macrophages and monocyte-differentiated macrophages from peripheral blood serves as a key mechanism of inflammation across organs, yet their phenotypic plasticity in ovarian pathologies, including POI, remains poorly understood. Here, we identify that SIRT5 deficiency decreases macrophage count by attenuating monocyte-macrophage differentiation. SIRT5 deficiency markedly attenuated follicular depletion and granulosa cell apoptosis, coinciding with reduced M1 macrophage infiltration and cytokine expression in the POI model. Mechanistically, we uncovered RAC2 as a novel succinylation substrate of SIRT5. SIRT5 deficiency elevated RAC2 succinylation, promoting its proteasomal degradation and thereby impairing CSF1R-driven macrophage differentiation and M1 polarization. Pharmacological inhibition of SIRT5 recapitulated these protective effects, preserving follicular integrity and suppressing macrophage-mediated inflammation. Our findings identify the SIRT5-RAC2 axis as a key regulator of ovarian immune homeostasis and establish SIRT5 as a proof-of-concept therapeutic target for POI.