Mitochondrial DNA Stress and cGAS-STING/NLRP3 Axis in Cr(VI)-Induced Target Organ Pyroptosis

Hexavalent chromium [Cr(VI)] is a highly toxic heavy metal pollutant widely distributed in the environment. It accumulates in target organs such as the liver and kidneys of animals, inducing serious tissue necrosis and inflammatory damage. Traditional toxicological studies have mainly focused on Cr(VI)-induced cell apoptosis; however, recent studies indicate that pyroptosis is a more critical driver of target organ damage. This review systematically clarifies that Cr(VI) generates reactive oxygen species (ROS) during intracellular reduction, resulting in mitochondrial stress. The ectopic leakage of mitochondrial DNA (mtDNA) into the cytoplasm is recognized as a damage-associated molecular pattern (DAMP) by the DNA sensor cGAS, thereby activating the cGAS–STING signaling pathway. Activated STING not only drives the transcription of pro-inflammatory cytokines but also promotes the assembly of the NLRP3 inflammasome, which in turn activates caspase-1 to mature IL-1β and IL-18 to trigger pyroptosis. Clarifying the toxicological mechanism of the mtDNA–cGAS–STING–NLRP3 axis not only fills the theoretical gap regarding Cr(VI)-induced inflammatory damage in animal target organs but also provides a new therapeutic target for clinical intervention.