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Immunology and Microbiology
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Molecular Science
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Abstract
Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic options and poor prognosis. Sorafenib, a multikinase inhibitor, is the first-line treatment for advanced HCC; however, the rapid emergence of drug resistance significantly limits its clinical efficacy. Our preliminary data indicate that Y-box binding protein 1 (YBX1) contributes to sorafenib resistance by reprogramming cholesterol metabolism. Specifically, YBX1 upregulates sterol regulatory element-binding protein 2 (SREBP2), enhancing cholesterol biosynthesis and accumulation while downregulating the cholesterol efflux transporter ABCA1. This metabolic alteration stabilizes receptor tyrosine kinases (RTKs), promoting Akt/mTOR signaling and sustaining drug resistance, thereby unraveling the connection between intracellular cholesterol accumulation, metabolic reprogramming, and resistance to therapeutics/treatments.
Methods: HCC cell lines (SK Hep1, HepG2, and HepG2 luc, Huh7 luc sorafenib-resistant derivatives) were used to investigate the YBX1–SREBP2 axis. Gene and protein expression analyses were performed using quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence. Functional assays, including proliferation, apoptosis, migration, and cytotoxicity, were performed following YBX1 overexpression or knockdown. Lipid accumulation was quantified using LipidSpot assays followed by confocal microscope, Oil Red O staining, and cholesterol assays. Pharmacological inhibition was assessed using the YBX1 inhibitor SU056 and the SREBP2 inhibitor betulin.
Results: YBX1 overexpression significantly enhanced SREBP2 expression and cholesterol biosynthesis, as indicated in oil red staining as well as lipid droplet fluorescence, while siRNA-mediated knockdown of YBX1 reduced these effects and accumulation of intracellular cholesterol. Sorafenib-resistant HCC cells exhibited increased YBX1, SREBP2, and drug-resistance markers (MDR1, PD-L1, and CD44), and higher sorafenib IC50 values than parental cells. Palmitic acid treatment further promoted lipid accumulation and resistance phenotypes in YBX1-overexpressing cells. Inhibition of YBX1 or SREBP2 reduced cholesterol accumulation and destabilized RTKs (EGFR and VEGFR) at the plasma membrane, thereby attenuating Akt/mTOR signaling. Combination treatment with sorafenib and SU056 or Betulin markedly decreased cholesterol-associated gene/protein expression compared to control.
Conclusions: Our findings identify YBX1 as a key regulator of metabolic and signaling reprogramming in HCC. The YBX1–SREBP2 axis promotes cholesterol biosynthesis and RTK stabilization, driving sorafenib resistance. Targeting this pathway restores drug sensitivity and represents a promising therapeutic strategy for overcoming treatment resistance in HCC.
Recommended Citation
Nagati, Veerababu; Salazar, Miguel; Tenugu, Swathi; Abuchard, Yamile; Pazzi, Ana Ayala; Bracho, Ricardo Pequeno; Kwabai, Dennis; and Tripathi, Manish K., "YBX1 Orchestrates SREBP2-Driven Cholesterol Metabolism to Confer Drug Resistance in Hepatocellular Carcinoma" (2026). Research Symposium. 16.
https://scholarworks.utrgv.edu/somrs/2026/posters/16
YBX1 Orchestrates SREBP2-Driven Cholesterol Metabolism to Confer Drug Resistance in Hepatocellular Carcinoma
Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic options and poor prognosis. Sorafenib, a multikinase inhibitor, is the first-line treatment for advanced HCC; however, the rapid emergence of drug resistance significantly limits its clinical efficacy. Our preliminary data indicate that Y-box binding protein 1 (YBX1) contributes to sorafenib resistance by reprogramming cholesterol metabolism. Specifically, YBX1 upregulates sterol regulatory element-binding protein 2 (SREBP2), enhancing cholesterol biosynthesis and accumulation while downregulating the cholesterol efflux transporter ABCA1. This metabolic alteration stabilizes receptor tyrosine kinases (RTKs), promoting Akt/mTOR signaling and sustaining drug resistance, thereby unraveling the connection between intracellular cholesterol accumulation, metabolic reprogramming, and resistance to therapeutics/treatments.
Methods: HCC cell lines (SK Hep1, HepG2, and HepG2 luc, Huh7 luc sorafenib-resistant derivatives) were used to investigate the YBX1–SREBP2 axis. Gene and protein expression analyses were performed using quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence. Functional assays, including proliferation, apoptosis, migration, and cytotoxicity, were performed following YBX1 overexpression or knockdown. Lipid accumulation was quantified using LipidSpot assays followed by confocal microscope, Oil Red O staining, and cholesterol assays. Pharmacological inhibition was assessed using the YBX1 inhibitor SU056 and the SREBP2 inhibitor betulin.
Results: YBX1 overexpression significantly enhanced SREBP2 expression and cholesterol biosynthesis, as indicated in oil red staining as well as lipid droplet fluorescence, while siRNA-mediated knockdown of YBX1 reduced these effects and accumulation of intracellular cholesterol. Sorafenib-resistant HCC cells exhibited increased YBX1, SREBP2, and drug-resistance markers (MDR1, PD-L1, and CD44), and higher sorafenib IC50 values than parental cells. Palmitic acid treatment further promoted lipid accumulation and resistance phenotypes in YBX1-overexpressing cells. Inhibition of YBX1 or SREBP2 reduced cholesterol accumulation and destabilized RTKs (EGFR and VEGFR) at the plasma membrane, thereby attenuating Akt/mTOR signaling. Combination treatment with sorafenib and SU056 or Betulin markedly decreased cholesterol-associated gene/protein expression compared to control.
Conclusions: Our findings identify YBX1 as a key regulator of metabolic and signaling reprogramming in HCC. The YBX1–SREBP2 axis promotes cholesterol biosynthesis and RTK stabilization, driving sorafenib resistance. Targeting this pathway restores drug sensitivity and represents a promising therapeutic strategy for overcoming treatment resistance in HCC.
