Selectivity matters: selective ROCK2 inhibitor ameliorates established liver fibrosis via targeting inflammation, fibrosis, and metabolism

• Published in: Communications biology Vol. 6; no. 1; p. 1176
• Main Authors: Zanin-Zhorov, Alexandra, Chen, Wei, Moretti, Julien, Nyuydzefe, Melanie S., Zhorov, Iris, Munshi, Rashmi, Ghosh, Malavika, Serdjebi, Cindy, MacDonald, Kelli, Blazar, Bruce R., Palmer, Melissa, Waksal, Samuel D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.11.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/89; 631/154/556; 64/60; 692/4020/4021/1607/1605; 96/106; 96/21; 96/31; 96/95; Adipocytes; Adipogenesis; AKT protein; Animals; Biology; Biomedical and Life Sciences; Fibroblasts; Fibrosis; High fat diet; Inflammation; Inflammation - drug therapy; Inflammation - pathology; Kinases; Life Sciences; Liver; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Metabolic pathways; Metabolism; Mice; Signal Transduction; Thioacetamide; TOR protein
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-05552-0

The pathogenesis of hepatic fibrosis is driven by dysregulated metabolism precipitated by chronic inflammation. Rho-associated coiled-coil-containing protein kinases (ROCKs) have been implicated in these processes, however the ability of selective ROCK2 inhibition to target simultaneously profibrotic, pro-inflammatory and metabolic pathways remains undocumented. Here we show that therapeutic administration of GV101, a selective ROCK2 inhibitor with more than 1000-fold selectivity over ROCK1, attenuates established liver fibrosis induced by thioacetamide (TAA) in combination with high-fat diet in mice. GV101 treatment significantly reduces collagen levels in liver, associated with downregulation of pCofilin, pSTAT3, pAkt, while pSTAT5 and pAMPK levels are increased in tissues of treated mice. In vitro, GV101 inhibits profibrogenic markers expression in fibroblasts, adipogenesis in primary adipocytes and TLR-induced cytokine secretion in innate immune cells via targeting of Akt-mTOR-S6K signaling axis, further uncovering the ROCK2-specific complex mechanism of action and therapeutic potential of highly selective ROCK2 inhibitors in liver fibrosis. Therapeutic administration of highly selective ROCK2 inhibitor reverses established liver fibrosis induced by chemical injury combined with high fat diet in mice via concurrent targeting of inflammatory, fibrotic and metabolic cellular pathways