Front Immunol. 2026 May 28;17:1831457. doi: 10.3389/fimmu.2026.1831457. eCollection 2026.
ABSTRACT
Oxidized low-density lipoprotein (oxLDL) is a central driver of inflammatory responses in atherosclerosis and triggers multiple forms of regulated cell death beyond classical apoptosis. Ferroptosis, characterized by iron-dependent lipid peroxidation (LPO), and pyroptosis, mediated by inflammasome-activated gasdermin D (GSDMD) pore formation, have emerged as critical contributors to plaque progression and instability. Recent evidence highlights a significant crosstalk between these two death modalities: the N-terminal fragment of GSDMD targets mitochondrial membranes to promote LPO, while ferroptotic byproducts-including oxidized phospholipids and 4-hydroxynonenal-activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. This bidirectional interplay establishes a positive feedback loop that amplifies vascular inflammation. This review summarizes the molecular mechanisms underlying oxLDL-induced ferroptosis and pyroptosis, emphasizes their interconnected regulatory networks, and discusses therapeutic strategies targeting this cell death axis. Understanding this integrated cell death network may provide new insights for resolving residual inflammatory risk in atherosclerotic cardiovascular disease.
PMID:42282966 | PMC:PMC13252779 | DOI:10.3389/fimmu.2026.1831457