MYCBP2-mediated HNF4α ubiquitination reprogrammed lipid metabolism in MASH-associated hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major global health burden, with metabolic dysfunction-associated steatohepatitis (MASH) emerging as a significant risk factor. The scarcity of effective pharmacological treatments for MASH and its progression to HCC underscores the need for deeper molecular insights. Our study identifies Myc-binding protein 2 (MYCBP2), an E3 ubiquitin ligase, as a potential tumor suppressor in MASH-related HCC. Through transcriptomic and proteomic analyses, we observed significant downregulation of MYCBP2 in HCC tissues. In vitro and in vivo experiments demonstrate that MYCBP2 inhibits HCC cell proliferation, migration, and invasion by modulating lipid metabolism pathways. Mechanistically, MYCBP2 promotes the ubiquitination and degradation of Hepatocyte Nuclear Factor 4 Alpha (HNF4α). This ubiquitination occurs via K33- and K48-linked polyubiquitin chains at lysines 300 and 307 of HNF4α. The results showed that MYCBP2 influences the expression of lipid metabolism-related genes and attenuates HNF4α's regulatory role in lipid metabolism through the mediated ubiquitination and degradation of HNF4α. Our findings elucidate the MYCBP2-HNF4α axis as a novel regulatory pathway in MASH-related HCC and highlight the broader implications of ubiquitination in cancer metabolism, offering a promising metabolic target for therapeutic intervention.