Molecular regulatory networks of microplastics and cadmium mediated hepatotoxicity from NAFLD to tumorigenesis via integrated approaches

作者：Yuhan Li, Yulun Jian, Jinjin Zhou, Min Zhang, Yanfeng Zhou, Ge Yang, Hui Wang, Wei Mu · 发表于：Ecotoxicology and Environmental Safety · 年份：2025 · DOI：10.1016/j.ecoenv.2025.118431 · 被引用次数：20 · 研究领域：Microplastics and Plastic Pollution、Nanoparticles: synthesis and applications、Air Quality and Health Impacts

Microplastics (MPs), as emerging environmental pollutants, not only possess inherent toxicity but also adsorb or carry other hazardous substances, such as the carcinogen cadmium (Cd), leading to more complex public health issues. Exposure to MPs and Cd has been shown to induce liver injury, with each pollutant triggering distinct toxicological pathways and pathological processes. In this study, Cd and MPs were selected as “stressors” to simulate the transformation from inflammation to tumorigenesis, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, and hepatocellular carcinoma (HCC), based on data from the Comparative Toxicogenomics Database (CTD) and Genecards. A comprehensive molecular spectrum of the precancerous-lesion-to-cancer cycles induced by individual and combined exposures was established. We also performed in vivo and in vitro experiments to validate these predicted molecular networks. Our findings demonstrated that Cd specifically induces the activation of ECM and cell proliferation-related genes ITGB5, COL3A1, and JUN, thereby driving liver cirrhosis and tumorigenesis. Conversely, MPs were found to predominantly regulate cell death-associated genes BAX and CASP8, which are involved in NAFLD and inflammation. More importantly, co-exposure of Cd and MPs exacerbates and accelerates hepatotoxicity, encompassing fibrosis and carcinogenesis. Therefore, we introduce regulatory cascades as novel initiating and key events within the Adverse Outcome Pa...