2. Academic Validation
  3. Selective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis

Selective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis

  • Cell. 2026 Apr 30;189(9):2663-2683.e26. doi: 10.1016/j.cell.2026.02.001.
Yan Hu 1,  Biao Yang 1,  Chengju Xiao 1,  Xinchun Yang 1,  Hua Zhang 1,  Pengbo Yang 1,  Xiao Du 1,  Guixiang Zhang 1,  Beibei Liang 2,  Nan Bai 2,  Daoguang Zhang 3,  Dongbo Wu 1,  Qinghua Luo 1,  Yangjing Teng 1,  Yumeng Chen 1,  Zhiqing Guo 1,  Chengjian Zhao 1,  Tinghong Ye 1,  Dong Chai 3,  Xiaolong Qi 4,  Weiting Zhong 3,  Jie Chen 1,  Haohao Dong 1,  Jinhang Gao 1,  Huanhuan He 5,  Junlei Chang 6,  Xuri Li 7,  Liang Peng 8,  Shahin Rafii 9,  Scott L Friedman 10,  Cheng Yi 11,  Yun Cai 12,  Yanping Zhao 13,  Hongjun Wang 14,  Chen Wang 15,  Zhongwei Cao 16,  Bi-Sen Ding 17
Affiliations

Affiliations

  • 1 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Respiratory Health and Multimorbidity, State Key Laboratory of Biotherapy, Division of Abdominal Tumor Multimodality Treatment, Division of Gastrointestinal Surgery, Department of Radiology, Center of Infectious Diseases, West China Second Hospital, West China School of Basic Medical Sciences & Forensic Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center, Chinese PLA General Hospital, Beijing 100853, China.
  • 3 Beijing Tide Pharmaceutical Co., Ltd., Beijing 100176, China.
  • 4 Center of Portal Hypertension, Zhongda Hospital, Southeast University, Nanjing 210009, China.
  • 5 Faculty of Health Sciences, University of Macau, Macau SAR 999078, China.
  • 6 Department of Neurology, The First Hospital of Jilin University, Changchun 130021, China.
  • 7 Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
  • 8 State Key Laboratory of Respiratory Health and Multimorbidity, National Respiratory Center, China-Japan Friendship Hospital, Beijing 10029, China.
  • 9 Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 10 Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 11 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Respiratory Health and Multimorbidity, State Key Laboratory of Biotherapy, Division of Abdominal Tumor Multimodality Treatment, Division of Gastrointestinal Surgery, Department of Radiology, Center of Infectious Diseases, West China Second Hospital, West China School of Basic Medical Sciences & Forensic Medicine, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 12 Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: [email protected].
  • 13 Beijing Tide Pharmaceutical Co., Ltd., Beijing 100176, China. Electronic address: [email protected].
  • 14 Beijing Tide Pharmaceutical Co., Ltd., Beijing 100176, China. Electronic address: [email protected].
  • 15 State Key Laboratory of Respiratory Health and Multimorbidity, National Respiratory Center, China-Japan Friendship Hospital, Beijing 10029, China; State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China. Electronic address: [email protected].
  • 16 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Respiratory Health and Multimorbidity, State Key Laboratory of Biotherapy, Division of Abdominal Tumor Multimodality Treatment, Division of Gastrointestinal Surgery, Department of Radiology, Center of Infectious Diseases, West China Second Hospital, West China School of Basic Medical Sciences & Forensic Medicine, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 17 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Respiratory Health and Multimorbidity, State Key Laboratory of Biotherapy, Division of Abdominal Tumor Multimodality Treatment, Division of Gastrointestinal Surgery, Department of Radiology, Center of Infectious Diseases, West China Second Hospital, West China School of Basic Medical Sciences & Forensic Medicine, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 41794026 DOI: 10.1016/j.cell.2026.02.001
Abstract

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.

Keywords

MASH; ROCK2; angiocrine; clinical trial; endothelial cell; fenestration; hepatic stellate cell; liver fibrosis; liver regeneration; vascular niche.

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