Ferroptosis-induced Secretomes promote Macrophage priming

Cells undergoing regulated cell death communicate with the immune system by releasing various protein and non-protein secretomes. Ferroptosis, a recently identified iron-dependent form of regulated cell death characterized by extensive lipid peroxidation, involves membrane rupture. However, a detailed analysis of ferroptotic secretomes and their biological activity has been lacking. In this study, we used a multi-omics approach to create an atlas of secretomes induced by ferroptosis and discovered a novel role in macrophage priming. Proteins known to function as damage-associated molecular patterns (DAMPs) and innate immune system components, such as MIF, heat shock proteins (HSPs), and chaperones, were released from ferroptotic cells. Non-protein secretomes with inflammatory functions included oxylipins and metabolites from the tricarboxylic acid (TCA) cycle and methionine cycles. Notably, when bone marrow-derived macrophages (BMDMs) were incubated with ferroptotic supernatants, they underwent transcriptional reprogramming indicative of priming. Exposure to ferroptotic supernatants also enhanced cytokine production in response to LPS. These findings provide a comprehensive catalogue of ferroptosis-induced secretomes and reveal their role in macrophage priming, which has significant implications for modulating inflammatory processes.