Metabolic Injury Niche Suppresses Macrophage Efferocytosis and Delays Recovery in Acute Kidney Injury 2258243

Introduction Efferocytosis, the clearance of apoptotic cells by macrophages, is essential for resolving inflammation and restoring tissue homeostasis following acute kidney injury (AKI). While impaired efferocytosis exacerbates injury, how the metabolic microenvironment modulates this function remains poorly defined. Given that AKI is characterized by metabolic reprogramming, identifying metabolic regulators of macrophage efferocytosis may reveal therapeutic targets for enhancing inflammation resolution and tissue repair. Methods We used a murine model of ischemia/reperfusion (I/R)-induced AKI to examine how local metabolic cues regulate macrophage efferocytosis. Single-cell RNA sequencing, lipidomic profiling, and biochemical assays were applied to identify transcriptional and signaling alterations. Efferocytic capacity and renal recovery were evaluated following genetic deletion and peptide inhibition of Regulator of G-protein Signaling 1 (RGS1). Results Post-injury accumulation of extracellular fatty acids emerged as a major driver of impaired macrophage efferocytosis. These lipids activated PPARα and induced RGS1 expression in a distinct efferocytosis-exhausted macrophage subset. Fatty acids also promoted RGS1 palmitoylation, enhancing its inhibition of Rac1, a key efferocytic GTPase. Genetic deletion of RGS1 restored Rac1 activity, rescued efferocytosis, and improved renal repair. Notably, a novel RGS1 palmitoylation-blocking peptide reproduced these effects, increasing efferocytosis, reducing proinflammatory cytokines, and accelerating kidney function recovery. Conclusion We identify a metabolic regulatory axis in which fatty acids transcriptionally and post-translationally suppress macrophage efferocytosis through RGS1. RGS1 functions as a metabolic checkpoint controlling inflammation resolution in AKI. Targeting RGS1 palmitoylation represents a promising strategy to restore efferocytosis and promote kidney repair.