Targeting the NLRP3/Caspase-1 pyroptotic pathway exacerbates insulin resistance upon exposure to nanoplastics with...

The surface chemical properties of nanoplastics (NPs), such as surface charge and functional groups, can markedly influence their toxicological effects. Recent studies have shown that NPs can disrupt glucose homeostasis. However, under metabolically susceptible conditions, such as hyperglycemia and metabolic dysfunction, differences in metabolic toxicity and the underlying mechanisms among surface-modified NPs remain unclear. In this study, zebrafish larvae and Hep G2 cells under high-glucose conditions were used to systematically compare the effects of PS-NPs, NPs-NH₂, and NPs-COOH on insulin resistance-like metabolic phenotypes. All three types of NPs aggravated insulin resistance-like metabolic abnormalities to varying degrees, with toxicity ranking as PS-NPs > NPs-NH₂ > NPs-COOH. Transcriptomic analysis and subsequent validation showed that NP exposure induced oxidative stress and impaired mitochondrial function, accompanied by an increase in cytosolic mtDNA copy number, and may promote enhanced NLRP3 inflammasome-related signaling. Molecular docking and molecular dynamics simulations predicted potential noncovalent interactions between the three NP types and NLRP3, providing preliminary theoretical clues for investigating the relationship between these potential interactions and NLRP3 inflammasome activation. Further investigation showed that NP exposure increased the expression of NLRP3, ASC, and total GSDMD, accompanied by elevated cleaved caspase-1 p20 levels and increased LDH and IL-1β release, collectively supporting enhanced NLRP3/caspase-1-related inflammatory and pyroptotic signaling. Intervention experiments showed that NLRP3 overexpression amplified these phenotypes, whereas NLRP3 knockdown by RNA interference or pharmacological intervention with disulfiram attenuated the associated inflammatory and pyroptosis-related responses and partially improved abnormalities in glucose, insulin, and insulin signaling-related indicators. Taken together, these findings support that mitochondrial damage and mtROS/cytosolic mtDNA-related danger signals may promote NLRP3/caspase-1-related inflammatory and pyroptotic signaling and contribute to insulin resistance-like metabolic dysregulation induced by NPs with different surface chemical properties in a high-glucose-susceptible context. This study provides a theoretical basis for assessing the health risks of NPs under high-glucose metabolic conditions and for screening potential molecular targets for intervention.