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TitleSelective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis.
Journal, issue, pagesCell, Vol. 189, Issue 9, Page 2663-2683.e26, Year 2026
Publish dateApr 30, 2026
AuthorsYan Hu / Biao Yang / Chengju Xiao / Xinchun Yang / Hua Zhang / Pengbo Yang / Xiao Du / Guixiang Zhang / Beibei Liang / Nan Bai / Daoguang Zhang / Dongbo Wu / Qinghua Luo / Yangjing Teng / Yumeng Chen / Zhiqing Guo / Chengjian Zhao / Tinghong Ye / Dong Chai / Xiaolong Qi / Weiting Zhong / Jie Chen / Haohao Dong / Jinhang Gao / Huanhuan He / Junlei Chang / Xuri Li / Liang Peng / Shahin Rafii / Scott L Friedman / Cheng Yi / Yun Cai / Yanping Zhao / Hongjun Wang / Chen Wang / Zhongwei Cao / Bi-Sen Ding /
PubMed AbstractLiver fibrosis is a prominent pathological process contributing to death from hepatic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). There is limited treatment for liver ...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.
External linksCell / PubMed:41794026
MethodsEM (single particle)
Resolution3.8 Å
Structure data

52224

9hjq

EMDB-52224, PDB-9hjq:
ROCK2 bound with TDI01
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

PDB-1ivi:
Crystal Structure of pig dihydrolipoamide dehydrogenase

Source
  • homo sapiens (human)
KeywordsCYTOSOLIC PROTEIN / inhibitor / kinase / TRANSFERASE

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