Hepatotoxicity Prediction and Multi-omics Reveal Mitochondrial and Lipid Metabolic Dysregulation in PM _2.5 -Induced Liver Fibrosis

Prolonged exposure to fine particulate matter (PM_2.5) has been linked to chronic liver injury and cancer. However, an alternative risk assessment method to prospective longitudinal studies of exposome-metabolome interactions for liver inflammation-associated hepatocellular carcinoma (HCC) is lacking. This study investigates the risk of long-term real-world PM_2.5 exposure in hepatocarcinogenesis through machine learning techniques. Shotgun mass spectrometry (MS) imaging data were acquired from mouse models across a continuum of fibrosis, cirrhosis, and HCC for training a multiclass classification model to identify "No Risk", "Cancer Risk", and "Cancer". Direct infusion-MS data from PM_2.5-exposed mouse livers were analyzed to classify risk. By integrating data-driven and knowledge-based approaches, 14 disease progression biomarkers were identified for modeling. Our results suggest that chronic real-world PM_2.5 exposure can induce liver fibrosis, presenting cancer risk. Incorporating metabolomics, lipidomics, and transcriptomics, we propose PM_2.5 exposure induces mitochondrial dysfunction, activates AMPK signaling, and increases ceramide accumulation, potentially mediating insulin resistance that contributes to nonalcoholic fatty liver disease and HCC progression. This work represents a significant advancement in assessing hepatotoxicity of environmental toxicants by reducing reliance on traditional animal testing methods. It also underscores the potential of emerging technologies in transforming our understanding of PM_2.5 exposure, paving the way for targeted interventions.