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Hepatic stellate cells (HSCs) are central to the development of liver fibrosis. Recently, the involvement of interleukin-17 (IL-17) and the NOD-like receptor protein 3 (NLRP3) inflammasome in hepatic pathologies has attracted significant research interest. Hepatocyte pyroptosis, a form of programmed cell death, is a critical factor in the occurrence of inflammation. The objective of this study was to investigate the specific roles of IL-17 and NLRP3 in the arsenic-induced activation of HSCs through hepatocyte pyroptosis. We pretreated MIHA cells with MCC950 (1 and 5 \u03bcM) and secukinumab (10 and 100 nM) for 4 h, then with NaAsO2 (25 \u03bcM) for 24 h at 37 \u00b0C under 5% CO2. After incubation, the cell-culture supernatant was collected and mixed with serum-free high-glucose DMEM medium in a 1:1 ratio to prepare the conditioned medium, which was subsequently used for the culture of LX-2 cells. The results showed that exposure to NaAsO2 induced hepatocellular pyroptosis, which led to the release of the inflammatory cytokines IL-18 and IL-1\u03b2 and subsequent activation of HSCs. Treatment with the inhibitors MCC950 and secukinumab significantly reduced the secretion of Extracellular matrix (ECM) components and attenuated HSC activation. These results demonstrate that blocking the IL-17 and NLRP3 signaling pathways significantly reduces HSC activation and attenuates hepatic fibrogenesis. These results provide novel molecular targets for the prevention and treatment of arsenic-related liver fibrosis.<\/jats:p>","DOI":"10.3390\/toxics13040287","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T03:32:53Z","timestamp":1744169573000},"page":"287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mechanistic Studies on the Role of IL-17\/NLRP3 in Arsenic-Induced Activation of Hepatic Stellate Cells Through Hepatocyte Proptosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Ting","family":"Hu","sequence":"first","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Chen","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Tian","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Luo","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangping","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, China"},{"name":"Guiyang Public Health Clinical Center, Guiyang 550003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1146\/annurev-pharmtox-051921-020936","article-title":"The Duality of Arsenic Metabolism: Impact on Human Health","volume":"63","year":"2023","journal-title":"Annu. 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