Targeting the YBX1-SREBP2 axis to overcome drug resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with limited treatment options and poor outcomes. Multikinase inhibitors remain the first-line therapy for advanced HCC. However, therapeutic resistance remains a significant challenge in HCC, and the molecular mechanisms underlying metabolic adaptation to drug resistance remain poorly understood. Here, we identify Y-box binding protein 1 (YBX1) as a key regulator of cholesterol metabolism that promotes tumor growth and drug resistance in HCC. Multi-omics and mechanistic analyses reveal that YBX1 transcriptionally activates Sterol Regulatory Element-Binding Protein 2 (SREBP2), a critical master regulator of cholesterol metabolism, and suppresses the cholesterol efflux transporter ABCA1, resulting in increased expression of cholesterol biosynthetic enzymes and intracellular cholesterol accumulation. Additionally, Cholesterol modulates TGFbeta signaling and is implicated in drug resistance. This metabolic rewiring stabilizes membrane receptor tyrosine kinases (RTKs) and sustains downstream PI3K/Akt/mTORC1 and EMT signaling pathways, thereby fostering the development of drug resistance. Genetic silence or pharmacological inhibition of YBX1 or SREBP2 with SU056/Betulin restores sorafenib sensitivity and reduces tumor growth. Clinically, higher levels of YBX1 and SREBP2 expression are associated with poor therapeutic response and decreased overall survival in patients with HCC. These findings uncover a YBX1/SREBP2/Cholesterol metabolic axis that mediates adaptive resistance, offering a new therapeutic target to overcome drug resistance in HCC. Keywords: Hepatocellular carcinoma, Drug resistance, YBX1, SREBP2, Cholesterol metabolism, Akt/mTOR signaling.