{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:58:56Z","timestamp":1790657936708,"version":"4.1.0"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Liver fibrosis, driven by metabolic dysfunction-associated steatohepatitis (MASH) and other chronic injuries, represents a global health crisis without approved pharmacological therapies. The Rho-associated coiled-coil kinases (ROCK1 and ROCK2), the principal effectors of Rho GTPases, have emerged as central nodes in fibrogenesis, yet the isoform-specific mechanisms and their translational potential remain incompletely defined. This review systematically dissects the divergent roles of ROCK1 and ROCK2 across the hepatic cellular landscape. We synthesize current knowledge on isoform-specific functions across major hepatic cell types, including hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), hepatocytes, macrophages, and immune cells, with emphasis on the evidence quality underlying each claim. ROCK2 appears to play a predominant role in the profibrotic vascular niche in several contexts, particularly in LSEC capillarization and HSC contraction; however, the contributions of both isoforms are fundamentally cell- and context-dependent. We discuss the evidence for ROCK isoform-specific functions, distinguishing among genetic, pharmacological, expression-based, and activation-based evidence. We further synthesize the complex crosstalk between ROCK signaling and the TGF-\u03b2\/Smad, Wnt\/\u03b2-catenin, Hippo\/YAP, and NOX4\/ROS networks. Crucially, we critically evaluate the translational pipeline\u2014from pan-ROCK inhibitors limited by systemic hypotension to next-generation selective ROCK2 inhibitors. A notable development in clinical translation is the selective ROCK2 inhibitor TDI01, which targets endothelial ROCK2 to attenuate fibrosis. In an extended, single-arm, open-label study of TDI01 in patients with liver fibrosis, fibrosis improvement was observed in five of six patients; however, given the small sample size, absence of a control group, and exploratory endpoints, these findings represent early signals that require validation in adequately powered randomized controlled trials. We further address unresolved controversies, including the dual hepatoprotective versus pro-steatotic functions of ROCK and the dose-dependent bidirectional regulation of HSCs migration, which challenge systemic inhibition strategies. Looking forward, we spotlight emerging frontiers such as cell-specific nanodelivery systems (vitamin A-liposomes, M6PHSA), PROTAC-mediated ROCK degradation, non-coding RNA therapeutics, and synergistic combinations with FXR, PPAR, and GLP-1 receptor agonists. This review provides a comprehensive blueprint for translating ROCK isoform biology into precision antifibrotic therapies.<\/jats:p>","DOI":"10.3389\/fphar.2026.1929302","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:41:13Z","timestamp":1790656873000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential functions of ROCK1 and ROCK2 in liver fibrosis and advances in targeted therapeutic strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Ting","family":"He","sequence":"first","affiliation":[{"name":"School of Pharmacy, Guangxi Medical University","place":["Nanning, Guangxi, China"]},{"name":"Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinqi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiemei","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0270288","DOI":"10.1371\/journal.pone.0270288","article-title":"The non-selective rho-kinase inhibitors Y-27632 and Y-33075 decrease contraction but increase migration in murine and human hepatic stellate cells","volume":"18","author":"Bachtler","year":"2023","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1097\/HEP.0000000000001608","article-title":"Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: november 2025 updates to AASLD practice guidance","volume":"83","author":"Bansal","year":"2026","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1016\/j.str.2003.11.002","article-title":"Protein kinase A in complex with rho-kinase inhibitors Y-27632, fasudil, and H-1152P: structural basis of selectivity","volume":"11","author":"Breitenlechner","year":"2003","journal-title":"Structure"},{"key":"B4","doi-asserted-by":"publisher","first-page":"154140","DOI":"10.1016\/j.metabol.2020.154140","article-title":"Epigenetic silencing of microRNA-125b-5p promotes liver fibrosis in nonalcoholic fatty liver disease via integrin \u03b18-mediated activation of RhoA signaling pathway","volume":"104","author":"Cai","year":"2020","journal-title":"Metabolism"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1016\/j.cell.2026.04.001","article-title":"Angiocrine signaling drives liver fibrosis: from mechanism to early clinical translation","volume":"189","author":"Cao","year":"2026","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1002\/hep.23931","article-title":"E-cadherin antagonizes transforming growth factor \u03b21 gene induction in hepatic stellate cells by inhibiting RhoA-dependent Smad3 phosphorylation","volume":"52","author":"Cho","year":"2010","journal-title":"Hepatology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1002\/hep.21375","article-title":"Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice","volume":"44","author":"Choi","year":"2006","journal-title":"Hepatology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"8747","DOI":"10.1080\/21655979.2022.2056690","article-title":"Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis","volume":"13","author":"Chong","year":"2022","journal-title":"Bioengineered"},{"key":"B9","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1042\/0264-6021:3510095","article-title":"Specificity and mechanism of action of some commonly used protein kinase inhibitors","volume":"351","author":"Davies","year":"2000","journal-title":"Biochem. 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