Epigenetic Reprogramming in Cadmium-Associated Liver Injury: Evidence, Mechanistic Insights, and Therapeutic Perspectives.

Abstract

Chronic cadmium (Cd) exposure is associated with adverse liver outcomes, including metabolic dysfunction-associated steatotic liver disease (MASLD), inflammation, and fibrosis, yet the mechanisms underlying persistent hepatic injury remain incompletely resolved. This review critically examines population-based and experimental evidence for Cd-associated epigenetic alterations, focusing on DNA methylation, histone modifications, N6-methyladenosine (m6A) RNA modification, and non-coding RNA regulation, and evaluates the extent to which these changes represent epigenetic dysregulation or remodeling versus relatively durable and functionally consequential reprogramming. Evidence is interpreted according to study design and level of functional validation. Current findings support context-dependent, model-specific roles for selected epigenetic regulators, with functional convergence on metabolic dysfunction, oxidative stress, inflammation, cell-death pathways, and fibrogenic activation, rather than a unified causal epigenetic program in humans. We further discuss cross-layer interactions, cell-type heterogeneity, emerging preclinical intervention strategies, and translational barriers, highlighting the need for longitudinal human studies, cell-resolved multi-omics, and target-specific functional validation.