Advanced Alcoholic Liver Disease Driven by a Pro-ferroptotic Diet.

Alcoholic liver disease (ALD) encompasses a spectrum of disorders, with advanced ALD-characterized by liver fibrosis-representing a severe stage with high mortality. The NIAAA ALD mouse model, a classical approach to study ALD by delivering alcohol through the Lieber-Decarli (LD) diet, typically does not progress to advanced ALD. We previously determined that ferroptosis causes hepatocellular injury in this model. Here we speculate that the enrichment of monounsaturated fatty acids (MUFAs) and vitamin E, which inhibit ferroptosis, and the lack of the pro-ferroptotic nutrient iron in the LD diet, may limit the progression of ALD by inhibiting ferroptosis. To test this hypothesis, we modified the LD diet to generate a pro-ferroptotic LD (PFLD) diet by depleting vitamin E, increasing dietary levels of iron, and replacing MUFAs with polyunsaturated fatty acids (PUFAs) that drive ferroptosis. Upon feeding alcohol through the PFLD diet, ∼30% of the mice developed liver fibrosis and macrosteatosis, hallmarks of advanced ALD. These pathological changes were associated with exacerbated ferroptosis, possibly driven by overaccumulation of PUFA-containing triglycerides. Our findings underscore the critical role of dietary lipid composition in determining ALD severity, and demonstrate that feeding alcohol through the PFLD diet may serve as a mouse model for advanced ALD.