Unravelling Mechanisms of Oxinflammation Induced by Heavy Metals

Exposure to heavy metals remains a significant public health concern due to their environmental persistence, bioaccumulation, and ability to interfere with essential cellular processes. A large part of metal-induced toxicity converges on the establishment of a chronic oxinflammatory state, driven by the reciprocal interaction between oxidative stress and inflammation. In this review, we synthesize current mechanistic evidence describing how toxic metals, including aluminum, arsenic, cadmium, lead, mercury, and nickel, disrupt redox homeostasis, impair cellular integrity, and activate inflammatory signaling pathways. These metals promote the excessive generation of reactive oxygen and nitrogen species through multiple mechanisms, including mitochondrial dysfunction, displacement of essential metal cofactors, and inhibition of antioxidant systems. The resulting molecular damage leads to the formation of damage-associated molecular patterns (DAMPs), which activate redox-sensitive transcription factors and inflammatory cascades. Importantly, emerging metabolomic evidence indicates that these processes are accompanied by coordinated metabolic reprogramming involving amino acid, lipid, and energy metabolism, as well as microbiota-derived metabolites. These metabolic alterations not only reflect cellular adaptation to stress but also actively contribute to the propagation of a systemic inflammatory state. An integrated oxinflammatory and metabolic response underlies structural and functional alterations across multiple organ systems, including the liver, kidneys, cardiovascular system, nervous system, and reproductive organs. Persistent exposure, even at low doses, sustains this often subclinical and chronic process, reinforcing the need to understand metabolic changes as central components of metal-induced toxicity.