Abstract
Drug resistance has emerged as a significant factor contributing to the dismal prognosis of patients with hepatocellular carcinoma (HCC). Since tyrosine kinase Inhibitors (TKIs) are the standard first-line therapy for advanced HCC, however, its effectiveness is significantly hindered by the development of drug resistance, the mechanisms of which are still not fully understood. This study aims to investigate the potential role of the transcription factor YBX1 in mediating drug resistance and to validate it as a potential therapeutic target in HCC. We identified increased YBX1 levels in human HCC patient cohorts and found that it is associated with tumor aggressiveness, metastasis, and poor survival, and is a key transcription factor contributing to drug resistance. Our results show that YBX1 overexpression confers sorafenib resistance in HCC. Elevating YBX1 levels in HCC cell lines increased cell survival, viability, and sorafenib IC50 values, as well as tumorigenic features and drug resistance markers. Conversely, siRNA-mediated knockdown of YBX1 reduced these effects. Sorafenib-resistant cells exhibited increased YBX1 and resistance markers. Inhibiting YBX1 significantly decreased the viability of resistant cells. In vivo studies demonstrated that inhibiting YBX1 with the small-molecule SU056 reduces tumor size. Thus, YBX1 is a promising target for extending drug resistance in HCC.