ArticleFrontiers in medicine2026
INVA8001, a novel and highly selective chymase inhibitor, ameliorates liver inflammation, fibrosis, and hyperplasia in Mdr2 knockout mice.
Article in Frontiers in medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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 ( 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 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 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.
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