Selective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis

Liver fibrosis is a prominent pathological process contributing to death from hepatic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). There is limited treatment for liver fibrosis. Here, we find that upregulation of Rho-associated coiled-coil containing kinase 2 (ROCK2) in liver endothelial cells (ECs) and perivascular hepatic stellate cells (HSCs) causes vascular niche dysfunction and triggers pro-fibrotic angiocrine signaling. Based on the vascular druggable target ROCK2, we developed its selective inhibitor showing anti-fibrotic potency in preclinical models and human patients. The ROCK2-selective inhibitor TDI01 restored vascular phenotype and alleviated fibrosis in rodent and minipig MASH models. A phase 1 clinical trial (ChiCTR2200058868) of TDI01 demonstrated its favorable pharmacokinetics and safety in humans. An extended clinical trial (ChiCTR2400082056) showed a trend toward reducing liver fibrosis in five of six patients after TDI01 treatment. Thus, we discover vascular ROCK2 as a pro-fibrotic target, and development of an inhibitor selectively targeting angiocrine ROCK2 may provide a treatment of liver fibrosis in human patients.