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<p>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 (<i>Folr2</i>) significantly attenuated experimental liver fibrosis in mice. In both human and murine fibrotic livers, FOLR2<sup>+</sup> 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.</p>

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Macrophage FOLR2 drives liver fibrosis via intercellular engagement of TGFβRII

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Man-man Yuan,
  • Bing-feng Zheng,
  • Jing-lin Wang,
  • Shuai-qi Xu,
  • Sheng-lan Wang,
  • Yang Tan,
  • Yong Feng,
  • Xian-chi Dong,
  • Qi-hua Zhu,
  • Jie Yan,
  • Qiang Xu,
  • Xing-xin Wu

摘要

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.