Transcriptomic Analysis Reveals an NRF2-Mediated Redox and Metabolic Reprogramming in Sorafenib-Resistant...

Area of Science:

• Hepatocellular Carcinoma Research
• Cancer Drug Resistance Mechanisms
• Molecular Oncology

Background:

• Sorafenib is a key treatment for advanced hepatocellular carcinoma (HCC) in patients ineligible for immunotherapy.
• Acquired resistance limits sorafenib's long-term efficacy, and its molecular drivers are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying acquired sorafenib resistance in HCC.
• To identify key molecular pathways and potential therapeutic targets for overcoming sorafenib resistance.

Main Methods:

• Established a murine model of acquired sorafenib resistance.
• Performed comparative RNA sequencing on sorafenib-sensitive and -resistant HCC cells.
• Utilized pathway analysis and Gene Set Enrichment Analyses (GSEA).
• Investigated the role of Nuclear Factor erythroid 2-related Factor 2 (NRF2) using pharmacological inhibition.

Main Results:

• Identified a distinct 1264-gene resistance signature in HCC cells.
• Observed downregulation of metabolic and intercellular signaling pathways.
• Found significant upregulation of redox-regulatory, mitochondrial, and cellular stress-response programs.
• Demonstrated upregulation of NRF2-regulated genes involved in antioxidant defense and ferroptosis suppression.
• Showed that NRF2 inhibition restored sorafenib sensitivity.

Conclusions:

• Acquired sorafenib resistance in HCC is characterized by stable NRF2-driven transcriptional and metabolic reprogramming.
• This reprogramming enhances antioxidant capacity, suppresses ferroptosis, and promotes tumor cell survival.
• Targeting NRF2-regulated redox metabolism presents a promising strategy to overcome sorafenib resistance in HCC.