Microplastics Exacerbate Cadmium-Induced Hepatotoxicity via the IRE1α/TXNIP/NLRP3 Axis-Driven Endoplasmic Reticulum Stress and Pyroptosis

Background: Microplastics (MPs) and cadmium (Cd) are widespread environmental pollutants posing significant health risks, but their combined hepatotoxic effects and underlying mechanisms remain poorly understood. Methods: Using in vivo and in vitro co-exposure models, we systematically investigated the impact of MPs on Cd-induced hepatotoxicity. The study assessed hepatic injury, oxidative stress, and inflammatory responses through transcriptomic analysis, histopathological examination, immunofluorescence, and quantitative real-time PCR. Pharmacological inhibition of endoplasmic reticulum stress with 4-phenylbutyric acid and selective blockade of IRE1α with MKC3946 were employed to dissect the signaling pathway. Results: Co-exposure to MPs and Cd significantly aggravated Cd-induced hepatic pathological damage, inflammation, and oxidative stress. Transcriptomic profiling revealed marked activation of the endoplasmic reticulum stress pathway and upregulation of pyroptosis-associated genes. Mechanistically, endoplasmic reticulum stress triggered pyroptosis via the IRE1α/TXNIP/NLRP3 signaling axis. Notably, inhibition of endoplasmic reticulum stress with 4-phenylbutyric acid, or selective blockade of IRE1α with MKC3946, effectively attenuated TXNIP/NLRP3 activation and the downstream pyroptotic response. Conclusions: MPs intensify Cd-induced hepatotoxicity by activating the IRE1α/TXNIP/NLRP3 pathway, leading to endoplasmic reticulum stress-driven pyroptosis. These findings provide a mechanistic framework for understanding the combined toxicity of microplastics and heavy metals, with important implications for environmental health risk assessment in animals and humans.