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

## TL;DR

This study shows that the SIRT5–RAC2 pathway influences macrophage behavior in ovarian inflammation, offering a potential treatment target for premature ovarian insufficiency.

## Contribution

The study identifies SIRT5 and RAC2 as a novel regulatory axis controlling macrophage differentiation and inflammation in premature ovarian insufficiency.

## Key findings

- SIRT5 deficiency reduces macrophage count and M1 polarization, decreasing ovarian inflammation.
- SIRT5 stabilizes RAC2 through desuccinylation, promoting macrophage differentiation and M1 polarization.
- Pharmacological inhibition of SIRT5 protects follicular integrity and reduces granulosa cell apoptosis in POI models.

## Abstract

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.

SIRT5 desuccinylates and stabilizes RAC2, activating CSF1R‐dependent signaling to drive monocyte differentiation into M0 macrophages and their polarization toward pro‐inflammatory M1 phenotypes in CTX‐induced premature ovarian insufficiency. Inhibiting the SIRT5‐RAC2 axis attenuates inflammation, reduces granulosa cell apoptosis, and preserves follicular development.