Multi-omics reveals PM2.5-Associated neuronal disulfidptosis: SLC3A2-OXSM imbalance, immune dysregulation, and electrophysiological dysfunction.

Particulate matter 2.5 (PM2.5) is a major environmental pollutant linked to neurological disorders through poorly understood mechanisms. We investigated whether PM2.5 induces disulfidptosis, a novel form of regulated cell death characterized by NADPH depletion and disulfide stress, in neuronal cells. Combining bioinformatics analysis of a PM2.5-exposed human cohort (GSE60767, n = 466) with in vitro experiments in primary neurons and in vivo validation in rats, we identified a characteristic molecular signature featuring SLC3A2 upregulation and OXSM downregulation (p < 0.01). This imbalance was associated with significant immune dysregulation (elevated memory B cells, CD8+ T cells, and Tregs; reduced monocytes) and metabolic disturbances (NADP+/NADPH imbalance, cystine overload). Direct evidence from non-reducing Western blot confirmed disulfide-mediated actin crosslinking in both cultured neurons and hippocampal tissues of PM2.5-exposed rats. Lentiviral manipulation revealed a unidirectional regulatory relationship wherein SLC3A2 knockdown (RNAi-SLC3A2) increased OXSM expression, while OXSM overexpression (OE-OXSM) did not affect SLC3A2 levels. Both RNAi-SLC3A2 and OE-OXSM interventions improved neuronal survival and normalized NADP+/NADPH ratios after PM2.5 exposure (200 μg/mL). However, RNAi-SLC3A2 significantly inhibited cystine uptake. Correspondingly, RNAi-SLC3A2 demonstrated more robust neuroprotection compared to OE-OXSM, as evidenced by greater improvements in neuronal viability and complete restoration of action potential amplitude. Collectively, these findings establish that PM2.5 induces neuronal disulfidptosis through hierarchical SLC3A2-OXSM axis dysregulation and identify this unidirectional relationship as a novel therapeutic target for PM2.5-associated neurological injury.