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.