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Sci.","Veterinary Sciences"],"abstract":"<jats:p>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 IRE1\u03b1 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 IRE1\u03b1\/TXNIP\/NLRP3 signaling axis. Notably, inhibition of endoplasmic reticulum stress with 4-phenylbutyric acid, or selective blockade of IRE1\u03b1 with MKC3946, effectively attenuated TXNIP\/NLRP3 activation and the downstream pyroptotic response. Conclusions: MPs intensify Cd-induced hepatotoxicity by activating the IRE1\u03b1\/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.<\/jats:p>","DOI":"10.3390\/vetsci13080748","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:45:26Z","timestamp":1785239126000},"page":"748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microplastics Exacerbate Cadmium-Induced Hepatotoxicity via the IRE1\u03b1\/TXNIP\/NLRP3 Axis-Driven Endoplasmic Reticulum Stress and Pyroptosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Yuxue","family":"Yang","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5971-2744","authenticated-orcid":false,"given":"Tong","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Deng","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Li","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-2158","authenticated-orcid":false,"given":"Fuhao","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Chongqing Fengdu Agricultural Science and Technology Development Group Co., Ltd., Chongqing 408200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiarui","family":"He","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangwei","family":"Xiang","sequence":"additional","affiliation":[{"name":"Chongqing Fengdu Agricultural Science and Technology Development Group Co., Ltd., Chongqing 408200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haocheng","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchuan","family":"Deng","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Zhong","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyao","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9898-5754","authenticated-orcid":false,"given":"Guangneng","family":"Peng","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4339-3778","authenticated-orcid":false,"given":"Dechun","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, 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