Decoding the diet-inflammation nexus: ferroptosis as a therapeutic target.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in the bidirectional interplay with chronic inflammation during disease progression. This review synthesizes evidence on how dietary components modulate chronic inflammation by targeting ferroptosis, revealing novel mechanisms through which dietary components like polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), vitamins, and phytochemicals dynamically balance lipid peroxidation and antioxidant defense. These components act via key pathways, including iron metabolism (iron transport pathway and ferritinophagy), lipid metabolism (FSP1/CoQ10 axis, lipophagy), and amino acid metabolism (SLC7A11/GPX4, transsulfuration). We highlight their dual roles in regulating inflammatory microenvironments and demonstrate their therapeutic potential in chronic inflammatory diseases such as diabetes, atherosclerosis, and neurodegeneration by targeting ferroptosis regulators (e.g. ACSL4, GPX4, and Nrf2). We further propose a multi-target synergistic strategy for dietary interventions to mitigate ferroptosis-driven inflammation. Our findings provide a theoretical foundation for precision nutrition in chronic disease management and outline future directions, including structure-activity relationship studies, clinical translation, and interdisciplinary approaches integrating multi-omics technologies. Bridging mechanistic insights with technological advances in multi-omics and biomarker development will enable targeted dietary approaches to disrupt the ferroptosis-inflammation axis, offering novel avenues for chronic disease prevention and management.