Asiatic Acid Mitigates PM 2.5 -Elicited Cardiomyocyte Pyroptosis via Suppression of mtDNA-Driven cGAS-STING-NLRP3...

Fine particulate matter (PM2.5) 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 PM2.5-induced cardiotoxicity in male BALB/c mice by interrupting a mitochondrial DNA (mtDNA)-driven pyroptotic cascade. Animals exposed to intranasal PM2.5 (16.2 mg·kg⁻¹, every 48 hours for 21 days) developed cardiac hypertrophy, contractile dysfunction, extensive fibrosis and ultrastructural mitochondrial damage concomitant with cytosolic release of mtDNA fragments (cytochrome c oxidase subunit I [CO1], NADH dehydrogenase subunit 1 [ND1], cytochrome b [Cytb]), down-regulation of mitochondrial transcription factor A (TFAM), and robust activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling (cGAS, STING, phosphorylated TANK-binding kinase 1 [p-TBK1], phosphorylated interferon regulatory factor 3 [p-IRF3]). Downstream, NOD-like receptor protein 3 (NLRP3) inflammasome assembly, caspase-1 cleavage, gasdermin D pore formation and maturation of interleukin-1 beta (IL-1β)/interleukin-18 (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 PM2.5-elicited cardiomyocyte pyroptosis and establish AA as a promising therapeutic agent against air-pollution-associated cardiovascular injury.