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Macrophage FOLR2 drives liver fibrosis via intercellular engagement of TGFβRII
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DOI：10.1038/s41401-026-01878-7.png)
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Abstract
En 中文
Hepatic stellate cells (HSCs) and macrophages are key regulators of liver fibrosis, yet their direct communication during fibrogenesis remains incompletely characterized. We showed that genetic deletion of folate receptor beta (Folr2) significantly attenuated experimental liver fibrosis in mice. In both human and murine fibrotic livers, FOLR2+ macrophages are frequently juxtaposed with activated HSCs. Functionally, FOLR2 expressed by reparative, but not M1 or scar-associated, macrophages promotes HSC activation in a contact-dependent manner. Mechanistically, FOLR2 binds to transforming growth factor beta receptor II (TGFβRII) on HSCs, sustaining transforming growth factor beta 1 (TGF-β1) signaling and driving fibrogenesis. Finally, the natural compound fraxinellone targets FOLR2, disrupts its interaction with TGFβRII, and attenuates HSC activation and liver fibrosis. These findings identify the FOLR2-TGFβRII intercellular interaction as a critical mediator of macrophage-HSC crosstalk and highlight its disruption as a promising therapeutic strategy against liver fibrosis.
Keywords:
liver fibrosis
reparative macrophage
intercellular interaction
FOLR2
TGFβRII
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