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Long\u2010term exposure to these pollutants is closely associated with hepatocellular carcinoma (HCC). However, the toxic targets and mechanisms underlying PFBA\u2010 and PFBS\u2010induced HCC remain unclear. To address this knowledge gap, this study employed a multifaceted approach encompassing network toxicology, molecular docking, and molecular dynamic simulation. Thirty\u2010six core targets associated with PFBA\u2010 and PFBS\u2010induced HCC were identified, and 12 key genes were initially screened through network toxicity analysis. Subsequently, based on the TCGA and ICGC datasets, three classical algorithms were applied to screen key genes: PPARG, ESR1, and ALB. Further exploration of the HCC\u2010related dataset from the GEO database identified six critical genes: PPARG, ESR1, CD36, ABCA1, ACACA, and ALB. Survival analysis and ROC analysis based on the TCGA dataset revealed and validated the strong association between the expression levels of key genes (PPARG, ESR1, and ACACA). Single\u2010gene GSEA showed that these three key genes may induce HCC through multiple biological pathways via interfering with the normal growth and development of hepatocytes and promoting inflammation and cell proliferation. Ultimately, molecular dynamics demonstrated the strong binding affinities between PFBA, PFBS, and the three protein receptors, with the best stability and flexibility of the interaction between PFBS and PPARG. These findings provide insights into the theoretical foundation for applying network toxicology, molecular docking, and molecular dynamic simulations in environmental pollutant research.<\/jats:p>","DOI":"10.1002\/jat.4818","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:39:44Z","timestamp":1748651984000},"page":"2005-2019","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Systematic Exploration of Potential Toxicity Targets and Molecular Mechanisms of Emerging Short\u2010Chain PFAS Substitutes: PFBA\u2010 and PFBS\u2010Induced Hepatocellular Carcinoma Based on Toxicity Network Analysis, Machine Learning, and Biomimetic Calculations"],"prefix":"10.1002","volume":"45","author":[{"given":"Zirui","family":"Zhang","sequence":"first","affiliation":[{"name":"Chengdu University of Traditional Chinese Medicine  Chengdu Sichuan 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