Core Viewpoint - The research highlights the pathogenic role of upregulated ROCK2 in liver fibrosis and emphasizes the importance of the vascular microenvironment in the progression of fibrosis, leading to the development of a selective ROCK2 inhibitor, TDI01, which shows promise in treating liver fibrosis [4][6][9]. Group 1 - The study reveals that the upregulation of ROCK2 in hepatic stellate cells and endothelial cells contributes to vascular microenvironment dysfunction and promotes fibrosis through angiocrine signaling [4][6]. - The research team developed TDI01, a highly selective ROCK2 inhibitor, which demonstrated good safety and antifibrotic potential in preclinical models and human liver fibrosis patients [4][6]. - TDI01 showed a trend of fibrosis reduction in 5 out of 6 liver fibrosis patients, with improvements in liver stiffness, collagen deposition, and fibrosis staging [6][9]. Group 2 - The study establishes ROCK2 as a druggable target for antifibrotic therapy in metabolic-associated steatotic liver disease (MASH) [9]. - The selective ROCK2 inhibitor TDI01 effectively blocked liver fibrosis in rodent and miniature pig models of MASH [9]. - The first-in-class drug development process from target discovery to clinical research is outlined, providing a theoretical and practical basis for targeting angiocrine functions in antifibrotic treatment [4][6].

Core Viewpoint - The article discusses the discovery of a novel membraneless organelle called Lipid-induced granule (LIG) in hepatocytes, which is induced by lipid accumulation and has implications for understanding liver fibrosis and potential intervention targets for fatty liver disease [3][9]. Group 1: Discovery and Characteristics of LIG - A new type of membraneless organelle, named Lipid-induced granule (LIG), has been identified in hepatocytes, revealing its characteristics, formation, and function [3]. - LIG is formed through the liquid-liquid phase separation (LLPS) of the DDX49 protein, which is induced by lipid metabolites, particularly arachidonic acid [10]. Group 2: Mechanism of Action - LIG plays a role in inhibiting the progression of metabolic dysfunction-associated fatty liver disease (MASLD) by feedback inhibition of the pro-fibrotic liver factor TIMP2 [10]. - The mechanism involves the recruitment of m5C-modified Timp2 mRNA and its reader YBX1 to LIG, which suppresses the translation of Timp2 mRNA, thereby inhibiting liver fibrosis [7][10]. Group 3: Clinical Relevance - The presence of LIG has been identified in human MASLD livers, and its abundance is negatively correlated with the progression of fibrosis [8]. - The global prevalence of MASLD is estimated to be 30% among adults, with its severe form, MASH, leading to liver fibrosis and significant health risks [6].