Acalabrutinib alleviates metabolic dysfunction–associated steatotic liver disease by regulating bile acid metabolism

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a global epidemic of chronic liver disease currently lacking effective treatment. Evaluating the therapeutic effects of existing drugs on MASLD is a time and cost-effective strategy. Bruton's tyrosine kinase (BTK) is an inflammatory signaling molecule playing an important role in the progression of MASLD. Aclabrutinib, a BTK inhibitor approved for treating mantle-cell lymphoma and chronic lymphocytic leukemia, has not been investigated for its potential to treat MASLD. This study examined the therapeutic effects and mechanisms of aclabrutinib on MASLD using a high-fat diet-induced mouse model. Results demonstrated significant alleviation of pathological parameters associated with MASLD upon administration of aclabrutinib. TSE PhenoMaster results revealed that aclabrutinib increased energy expenditure in mice. Furthermore, aclabrutinib upregulated the expression of genes associated with thermogenesis and lipolysis in adipose tissues. Additionally, it inhibited the transcription of genes related to lipid absorption in the small intestine and liver, while increasing the expression of hormone-sensitive lipase, hepatic nuclear factor 4 alpha and fibroblast growth factor 21 in the liver. Further analysis indicated that aclabrutinib promoted the alternative pathway of bile acid synthesis while restoring gut microbiota homeostasis. The altered bile acid profiles upregulated G protein-coupled bile acid receptor 1 expression in adipose tissues as well as vitamin D receptor expression in liver and small intestine. Our findings suggest that by regulating bile acid metabolism and gut microbiota, aclabrutinib may promote thermogenesis and lipolysis, thereby alleviating MASLD. This study provides novel insights into clinical applications targeting BTK for treating MASLD.