What question did this study set out to answer?

The aim is to explore the role of the YBX1-SREBP2 axis in drug resistance mechanisms in hepatocellular carcinoma.

April 5, 2026

Abstract 386: Targeting the YBX1-SREBP2 axis to overcome drug resistance in hepatocellular carcinoma.

VNVeerababu NagatiThe University of Texas Rio Grande Valley YAYanett AnayaThe University of Texas Rio Grande Valley MSMiguel SalazarThe University of Texas Rio Grande Valley

Key Points

The aim is to explore the role of the YBX1-SREBP2 axis in drug resistance mechanisms in hepatocellular carcinoma.
Identified YBX1 as a key regulator using multi-omics analyses.
Investigated SREBP2's role in cholesterol metabolism.
Used genetic and pharmacological inhibition of YBX1 and SREBP2 in experiments.
Analyzed the relationship between YBX1/SREBP2 expression and patient outcomes.
YBX1 activates SREBP2, increasing cholesterol biosynthesis and drug resistance.
Higher YBX1 and SREBP2 levels correlate with poor therapeutic response in HCC.
Inhibition of YBX1 or SREBP2 restores sensitivity to sorafenib, reducing tumor growth.

Abstract

Abstract 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 TGFβ 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. Citation Format: Veerababu Nagati, Yamile Abuchard Anaya, Miguel Salazar, Kaylee Renteria, Ricardo Pequeno Bracho, Manish K Tripathi. Targeting the YBX1-SREBP2 axis to overcome drug resistance in hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 386.

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