Integrated multi-omics and experimental analyses reveal VIPR1 as a potential mediator linking environmental bisphenol A exposure to MASH-HCC progression

Metabolic dysfunction-associated steatohepatitis-related liver cancer (MASH-HCC) is an increasingly important subtype of hepatocellular carcinoma, and environmental contaminants have been proposed as potential contributors to its progression. Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, has been implicated in metabolic dysfunction and liver injury. However, the molecular mechanisms linking BPA exposure to MASH-HCC remain incompletely understood. In this study, we employed an integrated framework combining transcriptomic analysis, weighted gene co-expression network analysis, machine learning, single-cell RNA sequencing, virtual knockout analysis, DrugReflector-based virtual screening, molecular docking, and experimental validation to investigate BPA-associated molecular alterations during MASH-HCC progression. VIPR1, AURKA, and CYP2C9 were identified as core candidates through integrative multi-omics analysis and machine-learning screening, with SHAP analysis showing the highest contribution of VIPR1 to model prediction. Single-cell and virtual perturbation analyses revealed hepatocyte-enriched expression patterns and prioritized YY1 as a potential upstream regulator of VIPR1. In vitro experiments further demonstrated that BPA exposure reduced nuclear YY1 abundance, accompanied by decreased VIPR1 expression under lipotoxic conditions, whereas YY1 overexpression partially restored VIPR1 expression. Moreover, VIPR1 overexpression attenuated, while VIPR1 knockdown enhanced, malignant-associated cellular phenotypes. Tasisulam was further identified as an exploratory transcriptomic reversal candidate and was associated with increased VIPR1 protein expression. Collectively, these findings identify a VIPR1-centered molecular vulnerability linking BPA exposure with malignant-associated alterations under lipotoxic conditions and provide candidate biomarkers and therapeutic targets for further investigation.