Macrophage-derived FGF21 Restrains Endometritis By Suppressing Inflammation and Promoting Repair Through FGFR1

Endometritis is a prevalent inflammatory disorder that impairs female fertility, yet effective therapeutic strategies remain limited. Although the fibroblast growth factor (FGF) family has been increasingly implicated in inflammatory diseases, its role in endometritis remains largely unexplored. Here, systematic profiling of the FGF family identified FGF21 as the most significantly upregulated member in inflamed uterine tissues. Mechanistically, FGF21 is predominantly derived from macrophages and is positively associated with inflammatory activation. Functional studies showed that genetic deletion of FGF21 markedly exacerbates uterine inflammation, whereas exogenous administration of recombinant human FGF21 (rhFGF21) alleviates tissue injury and suppresses inflammatory responses in lipopolysaccharide-induced endometritis. At the cellular level, FGF21 attenuates macrophage-mediated inflammation and promotes proliferation while inhibiting cell death in endometrial stromal cells. Importantly, these protective effects are recapitulated in a clinically relevant methicillin-resistant Staphylococcus aureus-induced model, where rhFGF21 exhibits robust dose-dependent therapeutic efficacy. Mechanistically, FGF21 exerts its effects through activation of fibroblast growth factor receptor 1 (FGFR1), and pharmacological inhibition of FGFR1 abolishes its anti-inflammatory and pro-repair functions. Collectively, our findings identify macrophage-derived FGF21 as a critical regulator of endometrial inflammation and tissue repair, and highlight the rhFGF21 as a potential therapeutic drug for endometritis.