Asiatic acid mitigates PM2.5-elicited cardiomyocyte pyroptosis via suppression of mtDNA-driven cGAS-STING-NLRP3 signalling

Fine particulate matter (PM 2.5 ) is a pervasive air pollutant strongly linked to cardiovascular morbidity, yet effective countermeasures remain elusive. Here, we report that the natural triterpenoid asiatic acid (AA) protects against PM 2.5 -induced cardiotoxicity in male BALB/c mice by interrupting a mitochondrial DNA-driven pyroptotic cascade. Animals exposed to intranasal PM 2.5 (16.2 mg kg -1 , every 48 h for 21 days) developed cardiac hypertrophy, contractile dysfunction, extensive fibrosis and ultrastructural mitochondrial damage concomitant with cytosolic release of mtDNA fragments (CO1, ND1, Cytb), down-regulation of TFAM, and robust activation of cGAS-STING signalling (cGAS, STING, p-TBK1, p-IRF3). Downstream, NLRP3 inflammasome assembly, caspase-1 cleavage, GSDMD pore formation and maturation of IL-1β/IL-18 were markedly elevated. Oral administration of AA (12.5 or 25 mg kg -1 from day 7) dose-dependently restored TFAM expression, reduced cytosolic mtDNA, blunted cGAS-STING-NLRP3 axis activation, attenuated pyroptosis and preserved cardiac architecture and function. These findings identify mtDNA-triggered cGAS-STING-NLRP3 signalling as a critical pathway underlying PM 2.5 -elicited cardiomyocyte pyroptosis and establish AA as a promising therapeutic agent against air-pollution-associated cardiovascular injury.