Mechanistic insights into bisphenol A – Induced liver fibrosis: Evidence of PPARγ downregulation and AKT1/FN1 signaling from multi-level analysis

作者：Qian He, Ying‐Chuan Yin, Yunyun Xu, Xue Tan, Yun-chao Wang, Wang Zhang · 发表于：Ecotoxicology and Environmental Safety · 年份：2025 · DOI：10.1016/j.ecoenv.2025.119068 · 被引用次数：7 · 研究领域：Liver Disease Diagnosis and Treatment、Peroxisome Proliferator-Activated Receptors、Fatty Acid Research and Health

Non-alcoholic fatty liver disease (NAFLD) has rapidly ascended to become the foremost chronic liver disorder globally, yet the precise molecular mechanisms by which pervasive environmental endocrine-disrupting chemicals (EDCs) contribute to its pathogenesis remain largely unelucidated. This study presents a robust, multi-scale analytical framework, integrating human population genetics with cell-type-resolved molecular pathology, to definitively establish bisphenol A (BPA) as a causal accelerant of NAFLD progression. Utilizing two-sample Mendelian randomization （MR） with publicly available GWAS summary statistics from over 300,000 participants, we support a compelling causal association between genetically proxied BPA exposure and elevated NAFLD susceptibility (β = 0.68, P < 5 × 10⁻¹⁰). Subsequent single-nucleus RNA sequencing (snRNA-seq) of 42 human liver samples delineated BPA-responsive transcriptional programs, predominantly localized within activated hepatic stellate cells (HSCs). Through the synergistic integration of weighted gene co-expression network analysis （WGCNA） and toxicogenomic profiling, we pinpointed a pivotal six-gene nexus-comprising PPARG, AKT1, FN1, HSP90AA1, CAV1, and ESR1-that orchestrates aberrant lipid metabolism, oxidative stress, and extracellular matrix remodeling, all critical hallmarks of NAFLD. Structure-based molecular docking simulations further revealed sub-micromolar affinities of BPA for key proteins within this nexus, including PPARγ, est...