Landmark Cell Study Identifies ROCK2 as Precision Target; TDI01 Demonstrates Liver Fibrosis Reversal in Early Clinical Data
核心洞察
A study published in Cell reveals that selective upregulation of ROCK2 (搜索) in liver endothelial cells and perivascular hepatic stellate cells drives liver fibrosis (搜索) progression.
Researchers developed TDI01, a highly selective ROCK2 (搜索) inhibitor that binds a hydrophobic pocket and induces an inactive "DFG-out" conformation, sparing ROCK1.
In a preliminary clinical study, 5 of 6 liver fibrosis (搜索) patients receiving 200 mg once daily for 24 weeks showed sustained reductions in liver stiffness and improved fibrosis biomarkers.
In April 2026, a groundbreaking study published online in the prestigious journal Cell unveiled a novel mechanism driving liver fibrosis (搜索) and introduced TDI01, a highly selective ROCK2 (搜索) inhibitor that has shown the ability to reverse liver fibrosis in early clinical testing. The research, titled "Selective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis," represents the first demonstration that selective upregulation of ROCK2 in liver endothelial cells and perivascular hepatic stellate cells (HSCs) serves as a core mechanism propelling fibrosis progression. The findings address a long-standing gap in mechanism-based targeted therapies for a condition that can progress to cirrhosis and liver cancer.
ROCK2 (搜索) Emerges as a Precision Therapeutic Target
Using RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analyses, the research team discovered that Rho-associated coiled-coil containing kinase 2 (ROCK2 (搜索)) is specifically highly expressed in endothelial cells (ECs) and perivascular HSCs of human fibrotic livers. Critically, ROCK2 protein levels increase progressively with fibrosis staging from F0 through F4. In contrast, its homolog ROCK1 showed no significant differential expression and is widely distributed across various cell types, clearly identifying ROCK2 as a precision target.
The team validated these findings using ROCK2 (搜索)-knockout mice (ROCK2^ΔEC/ΔEC^) in both carbon tetrachloride (CCl4)-induced liver fibrosis (搜索) and metabolic dysfunction-associated steatohepatitis (MASH) (搜索) models. Compared to control mice, the knockout models exhibited significantly reduced liver fibrosis severity, along with lower levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), confirming endothelial cell ROCK2 as a key driver of fibrosis.
TDI01: Rational Design and Preclinical Validation
Based on the crystal structure of ROCK2 (搜索), researchers designed and synthesized 686 compounds. Through screening for ROCK2-selective inhibitory activity, pharmacokinetic (PK) analysis, and toxicology testing, TDI01 was ultimately selected as the core drug candidate. Cryo-electron microscopy structural analysis revealed that TDI01 binds to a hydrophobic pocket of ROCK2, partially overlapping with the ATP-binding pocket, and induces ROCK2 to form an inactive "DFG-out" conformation. The L210 residue was identified as a critical site for achieving highly selective binding.
Preclinical studies across multiple liver fibrosis (搜索) models, including mice and minipigs, demonstrated that oral administration of TDI01 effectively reduced liver stiffness, decreased collagen deposition, reversed liver sinusoidal endothelial cell (LSEC) capillarization, and alleviated inflammation and steatosis, comprehensively restoring liver structure and function.
Encouraging Preliminary Clinical Results
Preliminary clinical data have been highly encouraging. Among 62 healthy volunteers who received TDI01, no severe adverse events were reported, with the drug demonstrating excellent pharmacokinetic properties and a good safety profile. In a study involving 6 liver fibrosis (搜索) patients treated with 200 mg once daily for 24 weeks, 5 patients showed sustained reductions in liver stiffness and significant improvements in key fibrosis biomarkers. Liver function tests tended to normalize, and liver biopsies revealed reduced collagen deposition. Notably, even patients with stage F4 cirrhosis exhibited histological improvement. The drug specifically inhibits ROCK2 (搜索) activity without affecting ROCK1, demonstrating excellent target selectivity.
Addressing a Significant Unmet Need
Liver fibrosis (搜索) is a key pathological process in chronic liver diseases such as MASH. Its core mechanism involves the abnormal activation and differentiation of HSCs into myofibroblasts, leading to excessive collagen secretion and disruption of liver structure. Current clinical treatment options remain limited, lacking clearly defined mechanism-based targeted therapies. The ROCK2 (搜索)-targeted approach represented by TDI01 offers a novel solution to this significant unmet clinical need.
The study, authored by Hu Y, Yang B, and Ding BS, was published in Cell (doi: 10.1016/j.cell.2026.02.001; PMID: 41794026). Cloud-Clone Corp. (搜索) supplied the MCP1/CCL2 ELISA Kit used in the study, which provided critical data for mechanistic validation and efficacy assessment by accurately measuring chemokine CCL2 levels.