Identification of a Prognostic Gene Signature Based on Lenvatinib Resistance in Hepatocellular Carcinoma with Functional Validation of the Key Gene CPB2

Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal form of liver cancer that necessitates the exploration of innovative strategies due to the limitations of current therapies, including high recurrence rates and drug resistance. Methods: Lenvatinib-resistant Huh7-LR and PLC/PRF/5-LR cell lines were established. RNA sequence analysis was performed to identify differentially expressed genes associated with lenvatinib resistance in HCC tissues. A prognostic model was constructed using Cox regression analysis incorporating eight prognosis-related genes. A nomogram was developed by combining clinical factors and risk scores. Functional validation of the key gene, CPB2, was performed to explore its role in HCC progression and lenvatinib resistance. Results: Lenvatinib-resistant Huh7-LR and PLC/PRF/5-LR cell lines exhibited significant resistance indices of 4.59 and 4.37, respectively. RNA sequence analysis revealed 82 genes associated with lenvatinib resistance that were differentially expressed in HCC tissues. The prognostic model stratified patients into high-risk and low-risk groups with significantly distinct overall survival outcomes (p = 3.057e-05). The nomogram demonstrated high concordance in predicting survival probabilities (AUC = 0.78). CPB2 has emerged as a core gene linked to lenvatinib resistance; low expression of CPB2 in HCC tissues is associated with poor prognosis and promotes HCC progression and lenvatinib resistance via inhibition of the MAPK signaling pathway. Conclusion: These findings underscore the importance of understanding lenvatinib resistance mechanisms, providing a foundation for future therapeutic strategies targeting CPB2, and advancing personalized treatment approaches for HCC. Keywords: hepatocellular carcinoma, lenvatinib resistance, risk signature, CPB2