Blocking TRIM47-mediated HNF4α degradation suppresses hepatocellular carcinoma progression

Previous studies have highlighted the downregulation of hepatocyte nuclear factor 4alpha (HNF4 α ) as a critical event in the pathogenesis of HCC. However, the mechanism of its degradation in HCC remains unclear. Tripartite motif 47 (TRIM47), a typical E3 ubiquitin ligase of the TRIM family, has been implicated in various tumors, yet its specific role in HCC progression is not fully elucidated. In this study, HNF4 α was identified as a potential target of TRIM47 by using co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis. TRIM47 facilitates the degradation of HNF4 α by mediating K48-linked ubiquitination at lysine 470. Abrogation of HNF4 α ubiquitination attenuated the promoting effect of TRIM47 on HCC malignancy. Molecular docking studies and Co-IP experiments revealed that K342, W349, and E353 of HNF4 α , along with K534 and K600 of TRIM47, are crucial for their interaction. A small molecule, CZ-2401, was selected as a potent inhibitor of the TRIM47–HNF4 α interaction through virtual screening and pharmacological activity validation. CZ-2401 effectively stabilizes HNF4 α protein in HCC cells and ameliorates TRIM47-driven HCC progression in vivo. Taken together, our research elucidates that targeting TRIM47–HNF4 α interaction is a potential therapeutic strategy for HCC, and identifies CZ-2401 as a potent inhibitor of HNF4 α degradation and a promising candidate for HCC therapy. TRIM47 binds to HNF4 α and facilitates its ubiquitination and degradation in HCC progression. CZ-2401 is a potent inhibitor of TRIM47–HNF4 α interaction and a promising candidate for HCC therapy.