YEATS2/TAK1 axis mediates TGF-β1 driven adaptive resistance to sorafenib in hepatocellular carcinoma.

Although Sorafenib can effectively prolong the median survival time of HCC patients with limited side effects, it may cause many patients to develop drug resistance, becoming a barrier to extending the overall survival time of HCC patients. Our previous research explored the mechanism of the TGF-β1 pathway in the occurrence and development of liver cancer; the mechanism of the TGF-β1 pathway in sorafenib resistance needs further exploration. Through the analysis of the related sequencing results of TGF-β1-treated Huh7 cells and sorafenib-resistant Huh7 cells in the GEO database, we identified YEATS2 as a TGF-β1-responsive gene that is consistently upregulated in sorafenib-resistant HCC models and associated with poor patient prognosis. Silencing YEATS2 significantly restored sorafenib sensitivity under TGF-β1-conditioned settings. Mechanistically, YEATS2 physically interacted with TGF-β-activated kinase 1 (TAK1), as supported by structural modeling, molecular dynamics simulation, and reciprocal co-immunoprecipitation. YEATS2 enhanced TAK1 activation and downstream stress-response signaling, whereas pharmacological or genetic inhibition of TAK1 abrogated YEATS2-mediated adaptive resistance to sorafenib. Our findings identify YEATS2 as a critical mediator of TGF-β1-driven adaptive resistance to sorafenib in HCC through functional activation of TAK1 signaling. Our findings identify the YEATS2-TAK1 axis as a mechanistically relevant pathway underlying TGF-β1-conditioned adaptive resistance to sorafenib in HCC.