Ferroptosis–Inflammation Crosstalk: Mechanistic Insights and Emerging Drug Targets

Abstract

Ferroptosis, a non-apoptotic form of regulated cell death characterized by iron accumulation and lipid peroxidation, has recently established its crucial role in inflammation and immune - related diseases. The current review aims at offering a comprehensive synthesis of the Interaction between ferroptosis and inflammation that governs the ferroptosis-inflammation axis, in which the inflammation environment and cell death process operates that can influence each other through difficult molecular pathways. In this context, this article discusses how inflammatory signalling pathways works, in terms of the inflammation environment, as exemplified by the pathway of the IFN-γ JAK/STAT1 axis, that regulates the ferroptotic pathway by inhibiting system Xc^- activity and reducing GPX4 function, and how ferroptotic cell death releases, in terms of how the spatiotemporal activation of oxidized lipid mediators and Damage–Associated Molecular Patterns (DAMPs) catalyses a process of NLRP3 inflammasome activation and myeloid cell polarization, by complying with a series of crucial metabolic checkpoints, including the ACSL-mediated lipid metabolism. Finally, we discuss the therapeutic strategies with particular emphasis on the opportunities afforded by next-generation Radical Trapping Antioxidants (RTAs) and iron-focused chelating agents. This overview understands the crosstalk of ferroptosis and inflammation as a keystone of immunometabolism which may provide new therapeutic opportunities of tackling intractable cancers, neurodegenerative disorders, and ischemic diseases.