Intermittent fasting mobilizes polyunsaturated fatty acid eicosapentaenoic acid inducing ferroptosis to suppress hepatocellular carcinoma progression

ABSTRACT: Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a leading cause of hepatocellular carcinoma (HCC), prompting ongoing efforts to understand its mechanisms and develop targeted therapies. Although dietary interventions such as fasting influence tumor growth, the underlying molecular pathways remain unclear. Here we show that intermittent fasting elevates eicosapentaenoic acid mobilization, which subsequently suppresses hepatocellular carcinoma progression by inducing ferroptosis. Mechanistically, this fatty acid acts as a signaling mediator by binding G protein-coupled receptor 120 (GPR120). This interaction activates the retinoid X receptor alpha (RXRα) and peroxisome proliferator-activated receptor alpha heterodimer (PPARα), upregulating cytochrome P450 oxidoreductase (POR) transcription and executing ferroptosis. We validate this pathway using orthotopic and genetic mouse models along with patient-derived organoids. With clinical data confirming that reduced cytochrome P450 oxidoreductase expression correlates with poor patient prognosis, these findings suggest eicosapentaenoic acid (EPA) supplementation as a potential fasting-mimetic strategy for disease management.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS15484 | MetaboLights | 2026-08-28

REPOSITORIES: MetaboLights