Next-Generation Redox Mediators: Itaconate, Nitro-Fatty Acids, Reactive Sulfur Species and Succinate as Emerging...

Oxidative stress is no longer viewed as a random imbalance between reactive oxygen species and antioxidants, but as a failure of an integrated redox network that connects metabolism, immunity, and metal homeostasis. Classical markers such as malondialdehyde and 4-hydroxynonenal define oxidative damage, yet they cannot explain how redox adaptation occurs or fails. Over the past decade, the discovery of regulated cell-death pathways (ferroptosis, cuproptosis) and emerging metabolic signals has revealed a new generation of adaptive redox mediators-including itaconate, nitro-fatty acids, reactive sulfur species and succinate-that act as electrophilic or persulfidating regulators rather than passive by-products of oxidation. This review integrates mechanistic, biochemical and clinical evidence to define how these mediators remodel the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1, nuclear factor kappa-light-chain-enhancer of activated B cells, and hypoxia-inducible factor 1-alpha axes, coordinate lipid-metal-sulfur cross-talk, and shape vulnerability or resistance to ferroptosis and cuproptosis. By combining deep molecular research with translational perspectives, we propose a unifying framework for predictive redox medicine based on composite biomarker panels and AI-assisted phenotyping. Understanding and quantifying these next-generation mediators will open new avenues for precision nutrition, drug development, and disease prevention-transforming oxidative-stress biology from a descriptive field into an actionable platform for human health.