TRIM31 promotes lenvatinib resistance and stemness in hepatocellular carcinoma through K48/K63-linked ubiquitination of GLDC.

Hepatocellular carcinoma (HCC) is a type of cancer with a high incidence rate and a high mortality rate and is a major cause of cancer-related death. The resistance of liver cancer cells to lenvatinib has become a crucial limitation that restricts the clinical therapeutic efficacy of HCC treatment. In the present study, we successfully establish lenvatinib-resistant liver cancer cell lines and perform transcriptome sequencing analysis, through which we identify the key gene tripartite motif containing protein 31 (TRIM31). As an E3 ubiquitin ligase harboring a RING domain, TRIM31 is capable of regulating the stability and biological functions of its substrate proteins through ubiquitination. Nevertheless, the specific role and underlying molecular mechanisms of TRIM31 in liver cancer cell stemness and lenvatinib resistance remain largely unclear. In this study, clinical sample analysis confirms its high expression in HCC tissues, which correlates with poor patient prognosis. The results of functional experiments demonstrate that TRIM31 knockdown inhibits HCC stemness and lenvatinib resistance, whereas TRIM31 overexpression significantly enhances these properties. Mechanistically, TRIM31 interacts with glycine decarboxylase (GLDC) and mediates K48- and K63-linked polyubiquitination through its RING domain, leading to GLDC protein degradation. GLDC degradation enhances HCC stemness and chemoresistance by relieving its suppression of PI3K/AKT/mTOR signaling. This study is the first to highlight the critical role of TRIM31 in HCC stemness and drug resistance, offering a potential new strategy for targeted therapy in HCC.