Cadmium-induced hepatotoxicity: Interconnecting molecular and cellular pathways.

Cadmium (Cd) is a persistent environmental toxicant with a prolonged biological half-life that accumulates in the liver following oral, intraperitoneal, or inhalational exposure. Experimental studies in murine models demonstrate that Cd-induced hepatotoxicity is driven by interconnected mechanisms involving oxidative stress, mitochondrial dysfunction, inflammation, DNA damage, energy imbalance, and disruption of lipid homeostasis. After entering hepatocytes via metal transporters, Intracellularly, Cd binds to metallothioneins as a primarly detoxification mechanism; however, excessive exposure overwhelms this detoxification system, allowing free Cd to accumulate in mitochondria and the endoplasmic reticulum (ER), thereby initiating cellular dysfunction. Oxidative stress represents a central mechanism of Cd toxicity. Cd increases reactive oxygen species, lipid peroxidation, and reactive nitrogen intermediates while suppressing antioxidant defenses, including superoxide dismutase, catalase, glutathione, and related enzymes. This impairment is closely linked to inhibition of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway, resulting in disrupted redox homeostasis and enhanced hepatic inflammation and fibrogenesis. Concurrently, Cd disrupts mitochondrial respiration, membrane potential, and bioenergetics, and activates ER stress signaling, further exacerbating metabolic dysfunction and potentially contributing to metabolic dysfunction-associated steatotic liver disease. Cd exposure also stimulates inflammatory pathways, including TLR4/NF-κB signaling and NLRP3 inflammasome activation, promoting cytokine production and immune cell infiltration. Moreover, multiple regulated cell death mechanisms such as apoptosis, ferroptosis, pyroptosis, and autophagy dysfunction along with genotoxic and epigenetic alterations, aggravate liver injury. Collectively, these findings highlight oxidative stress-mediated DNA damage, impaired repair mechanisms, and genomic instability as key contributors to Cd-induced hepatotoxicity.