Targeting mitochondrial permeability and cytosolic mtDNA release: Astragaloside IV suppresses cGAS-STING signaling pathway to protect against cadmium-induced hepatotoxicity.

Cadmium (Cd), a pervasive environmental toxicant, induces hepatotoxicity via mitochondrial damage and dysregulated inflammation. Astragaloside IV (AS-IV), the primary bioactive constituent of Astragalus membranaceus with antioxidative/anti-inflammatory properties, has an undefined regulatory role in the cGAS-STING axis during Cd-induced hepatic injury. In this study, the cytoprotective mechanisms of AS-IV against Cd-induced hepatotoxicity were investigated. The results showed that Cd exposure significantly impaired hepatocellular viability, induced mitochondrial dysfunction, promoted mitochondrial DNA (mtDNA) release into the cytosol, and thereby activated the cGAS-STING signaling pathway, while AS-IV intervention effectively mitigated Cd-induced mitochondrial perturbations, suppressed mtDNA efflux, and inhibited cGAS-STING pathway activation by attenuating mtDNA-dependent STING activation via suppressing cytosolic mtDNA release. Collectively, AS-IV exerts robust hepatoprotection against Cd toxicity via preservation of mitochondrial integrity, inhibition of cytosolic mtDNA translocation, and suppression of cGAS-STING-driven innate immune hyperactivation. These findings nominate AS-IV as a viable therapeutic countermeasure against heavy metal-induced organ damage.