STAT3 induced BRD9 activation promotes intrahepatic cholangiocarcinoma progression by enhancing CD36 controlled fatty acid metabolism

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile-duct malignancy with high mortality rates, poor sensitivity to chemotherapy, and poor prognosis. Treatment options are extremely limited. Bromodomain-containing protein 9 (BRD9) has been linked to the development of various cancers, and therapies targeting BRD9 have been found to be effective. However, the role of BRD9 in ICC has not been examined, and the mechanism underlying the effects of BRD9 in cancer remain unknown. In this study, we investigated the association between BRD9 expression and ICC tumor progression, finding that high levels of BRD9 were linked to ICC tumor growth and unfavorable prognosis. In terms of the mechanism, the STAT3-BRD9-CD36 axis was found to be involved in ICC tumor growth. High BRD9 expression was found to promote CD36 expression, enhancing fatty acid metabolism in tumor cells to enable more rapid proliferation, and high BRD9 levels were influenced by elevated STAT3 expression. Treatment with the CPT1A inhibitor Etomoxir further confirmed this mechanism by blocking lipid transfer into the mitochondria and suppressing fatty acid oxidation, resulting in lipid accumulation. In addition, it was found that inhibition of BRD9 reduced ICC tumor growth and could help overcome chemoresistance. Together, the results suggest the potential of BRD9 as a therapeutic target for intrahepatic cholangiocarcinoma and highlights its role in regulating fatty acid metabolism in cancer cells. • BRD9 expression is significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and independently predicts poor patient prognosis. • STAT3 directly activates BRD9 transcription, driving ICC cell proliferation, migration, and invasion. • BRD9 enhances fatty acid metabolism by promoting CD36 expression and regulating downstream lipid utilization pathways. • Targeting the STAT3–BRD9–CD36 axis suppresses ICC growth, suggesting a potential therapeutic strategy.