Frontiers in Medicine · Jun 9, 2026

INVA8001, a novel and highly selective chymase inhibitor, ameliorates liver inflammation, fibrosis, and hyperplasia in Mdr2 knockout mice

By Sharma S, Chen L, Zhou T et al.

AIMS: Mast cells (MCs) play a significant role in autoimmune diseases by mediating inflammatory responses, innate and adaptive responses, angiogenesis, and various pathological processes. In chronic liver diseases, MC numbers are significantly increased, and their degranulation leads to release of mediators, including chymase, which increases inflammation, activates hepatic stellate cells (HSCs), leading to fibrosis. Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease characterized by inflammation, fibrosis, ductular reaction, and eventual liver failure. Although MCs and chymase have been implicated in PSC pathogenesis, therapeutic targeting of chymase remains largely unexplored. In this study, we examined the efficacy of INVA8001, a highly selective and potent small-molecule chymase inhibitor in the Mdr2 knockout mouse (Mdr2-/- ) model of PSC. METHODS: We evaluated chymase and other MC markers in liver biopsy samples from late-stage PSC patients. The effect of chymase inhibition was evaluated using INVA8001 in Mdr2-/- mice. Ten-week-old male Mdr2-/- mice were injected intraperitoneally (IP) with 20 mg/kg of INVA8001 daily for 2 weeks and parameters of disease pathogenesis, including MC activation, inflammation, fibrosis, biliary pathology, and cholestasis were evaluated. Histological, immunohistochemical, biochemical, and molecular analyses were conducted to evaluate the effects of INVA8001 treatment in Mdr2-/- mice. RESULTS: Liver biopsies from explanted PSC patients showed increased numbers of chymase-positive cells compared with control samples (collected from non-diseased patients). INVA8001 treatment reduced chymase activity and was associated with decreased MC accumulation, inflammation, histological damage, fibrosis, ductular reaction, and biliary senescence in Mdr2-/- mice. DISCUSSION: The current data show the pathophysiological role of chymase in PSC and the impact of a selective chymase inhibitor on PSC disease pathogenesis. These findings may have broader implications for MC-driven diseases such as chronic urticaria, atopic dermatitis, asthma, metabolic dysfunction-associated steatohepatitis (MASH), and eosinophilic gastrointestinal diseases, among others, where chymase is central to the disease pathogenesis. CONCLUSION: Our findings suggest that chymase is strongly associated with PSC pathogenesis and that INVA8001 may represent a promising new therapeutic candidate for hepatobiliary disorders, including PSC. Chymase inhibition simultaneously targets MC activation, inflammation, fibrosis, and biliary senescence, and offers a multifaceted approach to treating PSC and other MC-related disorders.

doi.org/10.3389/fmed.2026.1840071 Open access PubMed 42344483 Interventions