Abstract
Sorafenib and lenvatinib are frontline treatments for advanced hepatocellular carcinoma (HCC). While lenvatinib surpasses sorafenib in efficacy and tolerability, resistance remains a significant clinical challenge. Recent research highlights the potential of TRIM family proteins in modulating lenvatinib resistance in HCC, necessitating a deeper understanding of their specific mechanisms. In this study, we screened TRIM family genes differentially expressed in lenvatinib-resistant cells using the GEO database, verifying their expression through qRT-PCR and identifying TRIM29 as a key target. Clinical samples were analyzed to assess TRIM29 expression, clinical significance, and its correlation with lenvatinib treatment efficacy. Stable TRIM29 overexpression in SK-Hep1 and LM3 cells was confirmed by Western blotting. The impact of TRIM29 on lenvatinib sensitivity in liver cancer cells was evaluated using colony formation assays, CCK8, flow cytometry, and in vivo experiments. Transcriptome sequencing, mass spectrometry, and co-immunoprecipitation (CO-IP) were employed to elucidate TRIM29's regulatory mechanisms. Results from the GEO database indicated significant upregulation of TRIM29, TRIM50, TRIM31, and TRIM9 in HUH7-resistant cells, with qRT-PCR confirming TRIM29 as markedly upregulated. In 112 liver cancer patients clinical samples, TRIM29 expression was significantly higher in patients with stable disease or partial response to lenvatinib compared to those with disease progression. High TRIM29 expression was associated with longer overall survival and recurrence-free periods in HCC patients. Mechanistic studies revealed that TRIM29 enhances lenvatinib sensitivity by degrading YBX1 through ubiquitination, thereby inhibiting the PI3K/AKT signaling pathway and reversing resistance. These findings suggest that TRIM29 is a promising therapeutic target for overcoming lenvatinib resistance in HCC. CONCLUSION: TRIM29 degrades YBX1 through ubiquitination, thereby inhibiting the PI3K/AKT signaling pathway and reversing lenvatinib resistance in HCC. TRIM29 can serve as an independent prognostic indicator of survival and recurrence in HCC patients, and it may provide new avenues for developing innovative treatment strategies for HCC.