Methionine restriction attenuates renal injury by suppressing macrophage polarization via IRF1 downregulation

Abstract

Ischemia–reperfusion injury is a leading cause of acute kidney injury and delayed graft function following kidney transplantation. Macrophages are key mediators of ischemia–reperfusion injury-induced inflammation and tissue remodelling; however, the metabolic mechanisms underlying their activation remain poorly defined. In this study, we demonstrate that methionine restriction impaired the polarization of bone marrow-derived macrophages toward both M1 and M2 phenotypes. Mechanistically, methionine restriction led to decreasing H3K4me3 enrichment at the Irf1 promoter, thereby downregulating IRF1 expression and impairing macrophage polarization. Dietary methionine restriction reduced the infiltration of inflammatory macrophages, alleviated tubular damage, and attenuated early interstitial fibrosis in a mouse model of renal ischemia–reperfusion injury. These findings identify methionine metabolism as a key immunometabolism checkpoint in renal ischemia–reperfusion injury and suggest that dietary methionine restriction may serve as a potential therapeutic strategy to attenuate inflammation and fibrosis in ischemic kidney injury.