Heavy Metal–Induced Hepatic Inflammation: Mechanistic Pathways, Epidemiological Evidence, and the Emerging but Unvalidated Role of Plant-Based Dietary Strategies

Abstract

Background: Chronic exposure to cadmium (Cd), lead (Pb), and mercury (Hg) has been associated with hepatic inflammation and metabolic liver dysfunction in experimental and epidemiological studies. Experimental evidence indicates that these metals can disrupt redox homeostasis, impair mitochondrial function, suppress nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant responses, and activate inflammatory signaling pathways, with potential relevance to metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Methods: PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library were searched for peer-reviewed English-language literature published from January 2000 to March 2026. Epidemiological, experimental, and interventional studies linking Cd, Pb, or Hg exposure to hepatic outcomes, as well as potentially relevant plant-derived bioactive compounds, were considered. Results: Human studies report associations between metal exposure and hepatic outcomes, although the evidence is largely observational and affected by important confounders. Polyphenols, flavonoids, alkaloids, and terpenoids show antioxidant, anti-inflammatory, and metal-chelating effects predominantly in vitro and in animal models, with limited clinical validation. Conclusions: Current evidence supports the liver as a potentially important target of chronic metal exposure; however, the available human evidence remains largely observational and does not establish causality. The hepatoprotective effects of plant-derived compounds remain predominantly preclinical and require validation in human populations. Future longitudinal and interventional studies should incorporate exposure assessment and appropriate control of confounding before clinical or dietary recommendations can be established.