ANXA1-mediated mTOR/FABP4 Inhibition Drives Antifibrotic Macrophage Reprogramming in Lupus Nephritis

Inflammation and fibrosis are central pathological processes in lupus nephritis (LN). Annexin A1 (ANXA1), a protein highly expressed in myeloid cells, is a key modulator of inflammation and fibrosis. In this study, we found that renal ANXA1 expression was elevated in LN patients and correlated positively with the severity of fibrosis. Single-cell RNA sequencing identified a distinct monocyte-derived <i>Anxa1⁺Spp1⁺</i> macrophage subset that expands during nephritis and displays a profibrotic transcriptional signature. Mechanistically, ANXA1 signals <i>via</i> the FPR2/ALX receptor to inhibit mTOR/FABP4 activity in macrophages, enhance fatty acid oxidation, and thereby drive a polarization shift toward an antifibrotic phenotype. Consequently, treatment with the ANXA1-mimetic peptide Ac2-26 attenuated macrophage-driven fibrosis, reduced renal lipid accumulation, and ameliorated kidney injury in lupus-prone mice. These findings underscore the critical role of ANXA1 and <i>Anxa1⁺Spp1⁺</i> macrophages in renal fibrosis progression, offering novel therapeutic targets for LN.