OMA1-Mediated Mitochondrial Stress Exacerbates PANoptosis in Macrophages Via the mtROS-ZBP1 Axis in Coal Dust-Exposed Asthma

This study aimed to elucidate the mechanisms by which coal dust exposure (CDE) exacerbates asthma, focusing on macrophage mitochondrial dysfunction and programmed cell death, and identifying the key regulatory molecules involved. Control, CDE, Asth, and CDE+Asth mouse models were established to evaluate lung function, inflammatory cells and cytokines in bronchoalveolar lavage fluid, histopathological changes, and macrophage polarization. Mitochondrial function and PANoptosis activation in macrophages were assessed. In vitro validation was performed using OMA1‑knockout (KO) macrophages and carbonyl cyanide m-chlorophenyl hydrazone (CCCP) rescue experiments, and in vivo validation using myeloid‑specific OMA1-KO mice. OMA1 expression, mitochondrial stress markers, and PANoptosis‑related molecules were measured in peripheral blood mononuclear cells (PBMCs) and serum from patients with coal dust-exposed asthma, followed by correlation analyses. The CDE+Asthma group showed the most severe lung dysfunction, airway inflammation, tissue remodeling, and macrophage polarization imbalance, along with significant mitochondrial dysfunction and PANoptosis. OMA1 was upregulated in model lungs and patient PBMCs. OMA1‑KO alleviated mitochondrial damage and PANoptosis in vitro, an effect reversible by CCCP and dependent on Z-DNA binding protein 1 (ZBP1) downregulation. Myeloid‑specific OMA1-KO attenuated CDE+Asthma‑induced pathology in vivo. In patients, OMA1 correlated positively with mitochondrial stress markers and negatively with lung function; serum PANoptosis markers were elevated. In conclusion, CDE exacerbates pulmonary inflammation and injury in asthma by aggravating macrophage mitochondrial dysfunction and PANoptosis, with OMA1 serving as a key regulatory molecule in this pathological axis.