Lipid Remodeling Links Iron And Adiponectin To Ferroptosis, Inflammation, And Metabolic Regulation.

Abstract

Cardiometabolic diseases (CMD) impose a substantial global health burden marked by chronic metabolic stress, oxidative imbalance, and low-grade inflammation. While disturbances in iron metabolism, lipid metabolism and adipokine signaling are increasingly recognized in CMD, how these processes converge to influence cellular vulnerability and intercellular metabolic regulation remains incompletely understood. This dissertation investigated the roles of iron-induced ferroptosis and adiponectin-associated extracellular vesicles (EVs) in linking lipid remodeling to cardiometabolic pathology. Study 1 demonstrated that enrichment of ω-6 polyunsaturated fatty acid (PUFA)–containing membrane phospholipids, particularly phosphatidylethanolamines, markedly sensitized cardiomyocytes to iron-induced lipid peroxidation, mitochondrial dysfunction, sterile inflammatory signaling, and ferroptotic cell death. These findings establish membranous lipid composition, rather than lipid abundance alone, as a critical determinant of cellular vulnerability under metabolic stress. Building on this mechanistic framework, Study 2 extended lipid-mediated cellular vulnerability to the level of intercellular communication. Integrated EV lipidomic and functional analyses in murine models and human metabolic syndrome cohorts identified a conserved PUFA-enriched EV lipid signature associated with adiponectin deficiency. EVs carrying this lipid signature modulated recipient cell phenotypes by promoting oxidative and inflammatory signaling in macrophages, impairing mitochondrial energetics and insulin signaling in skeletal muscle cells, and disrupting glucose-stimulated insulin secretion in pancreatic β-cells. These findings indicate that EV lipid composition can regulate metabolic and inflammatory responses in recipient cells. Collectively, these findings demonstrate that metabolic stress is associated with PUFA-driven membrane lipid remodeling at the cellular level and with corresponding changes in the lipid composition of EVs. Adiponectin deficiency is linked to EV lipid remodeling and altered metabolic and inflammatory regulation in recipient cells. Together, these observations identify lipid remodeling, iron homeostasis, and EV-associated pathways as interconnected features of CMD biology with implications for biomarker discovery.