Macrophages diverge into profibrotic SAMs and proresolving ReM2 cells to regulate liver fibrosis
- Dezhen Zhang
- Xinjie Liu
- Dong Ma
- Lingling Liao
- Fugang Duan
- Yiming Wang
- Tongzhen Zhang
- Jiang Liu
- Wei Dong
- Junfei Jin
- Zhenhua Luo
- Haining Zhou
2026-08-21
A central question in liver fibrosis is how macrophages, key regulators of inflammation and tissue repair, are divergently programmed to either promote scar formation or drive its resolution. Here, we identify a macrophage axis that governs this balance. While scar-associated macrophages (SAMs) promote fibrogenesis through cytokine-mediated activation of hepatic stellate cells, a previously uncharacterized macrophage subset, termed ReM2, orchestrates fibrosis regression. ReM2 arises from circulating monocytes following liver injury, accumulates during fibrogenesis, and peaks during the resolution phase. Mechanistically, ReM2-dependent fibrosis regression requires the expression of specific receptors, including FCGR4 and ITGA4, which may mediate this effect by enabling direct recognition and phagocytic clearance of collagen I and fibronectin from the extracellular matrix. These findings reveal a functional divergence of monocyte-derived macrophages that governs fibrosis progression vs. resolution and suggest that therapeutic rebalancing of the SAM–ReM2 axis may represent a promising strategy for treating liver fibrosis.