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bioRxiv · 10.64898/2026.05.25.727562

M1 macrophage-mediated lymphangiogenesis aggravates liver fibrosis via MDK/YAP signaling pathway

Wang, D.·Long, D.·Zhao, Y.·Li, D.·Xiong, F.·Huang, Z.·Yang, L.·Zheng, Q.·Chen, Y.·Zhou, Y.·Feng, L.
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Abstract

BackgroundLymphangiogenesis plays a critical role in various liver diseases, yet its function in liver fibrosis remains controversial. This study aimed to explore the role of lymphangiogenesis in liver fibrogenesis and its underlying regulatory mechanisms. MethodsLiver fibrotic mice were established by carbon tetrachloride (CCl4) or Thioacetamide (TAA)-induced injection or bile duct ligation. Lymphatic vessels were marked by podoplain (Pdpn) staining in mice and D2-40 staining in clinical samples. Lymphatic vessels area and density were measured to indicate lymphangiogenesis. Multiplexing immunohistochemistry was used to detect co-localization of proteins. ResultsIn the present study, we first verified increased lymphangiogenesis in human and murine fibrotic livers. Afterwards, we identified VEGFC rather than VEGFD as the primary driver of lymphangiogenesis in liver fibrosis. Furthermore, we demonstrated that M1 macrophages serve as the major source of VEGFC. Founctional studies revealed that VEGFC-mediated lymphangiogenesis exacerbates hepatic fibrosis, while its inhibition alleviated fibrosis. Bioinformatic analysis uncovered Midkine (MDK) as a key downstream of lymphangiogenesis. Both in vivo and in vitro studies confirmed that exogenous MDK promotes liver fibrosis via activating hepatic stellate cells (HSCs), whereas MDK inhibition counteracts the profibrotic effects of VEGFC-induced lymphangiogenesis. Importantly, we discovered that MDK activates HSCs through the Hippo/YAP signaling pathway. ConclusionsM1 macrophage-mediated lymphangiogenesis aggravates liver fibrosis via MDK secretion, which activates HSCs. These findings provide novel insights into coordinated crosstalk between macrophages, lymphatic endothelial cells and HSCs in liver fibrosis and suggest lymphangiogenesis and MDK as potential therapeutic targets for fibrotic liver diseases.

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Wang, D., Long, D., Zhao, Y., Li, D., Xiong, F., Huang, Z., Yang, L., Zheng, Q., Chen, Y., Zhou, Y., Feng, L.. 2026-05-27. M1 macrophage-mediated lymphangiogenesis aggravates liver fibrosis via MDK/YAP signaling pathway. https://doi.org/10.64898/2026.05.25.727562

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