Ambient fine particulate matter provokes multiple modalities of cell death via perturbation of subcellular structures

Fine particulate matter (PM2.5) is increasingly recognized for its detrimental effects on human health, with substantial evidence linking exposure to various forms of cell death and dysfunction across multiple organ systems. This review examines key cell death mechanisms triggered by PM2.5, including PANoptosis, necroptosis, autophagy, and ferroptosis, while other forms such as oncosis, paraptosis, and cuprotosis remain unreported in relation to PM2.5 exposure. Mitochondria, endoplasmic reticulum, and lysosomes emerge as pivotal organelles in the disruption of cellular homeostasis, with mitochondrial dysfunction particularly implicated in metabolic dysregulation and the activation of pro-apoptotic pathways. Although PM2.5 primarily affects the nucleus, cytoskeleton, mitochondria, endoplasmic reticulum, and lysosomes, other organelles like ribosomes, Golgi apparatus, and peroxisomes have received limited attention. Interactions between these organelles, such as endoplasmic reticulum-associated mitochondrial membranes, lysosome-associated mitophagy, and mitochondria-nuclei retro-signaling may significantly contribute to the cytotoxic effects of PM2.5. The mechanisms of PM2.5 toxicity, encompassing oxidative stress, inflammatory responses, and metabolic imbalances, are described in detail. Notably, PM2.5 activates the NLRP3 inflammasome, amplifying inflammatory responses and contributing to chronic diseases. Furthermore, PM2.5 exposure disrupts genetic and epigenetic regulation, often resulting in cell cycle arrest and exacerbating cellular damage. The composition, concentration, and seasonal variability of PM2.5 modulate these effects, underscoring the complexity of PM2.5-induced cellular dysfunction. Despite significant advances in understanding these pathways, further research is required to elucidate the long-term effects of chronic PM2.5 exposure, the role of epigenetic regulation, and potential strategies to mitigate its harmful impact on human health.