Selenium regulates pyroptosis through the ROS-mtDNA-cGAS-STING axis to alleviate trimethyltin chloride-induced...

Trimethyltin chloride (TMT) is a highly toxic and environmentally ubiquitous organotin compound. Selenium (Se) mitigates toxin-induced injury by alleviating oxidative stress, whereas mitochondrial DNA (mtDNA) leakage activates pyroptosis and inflammation via the mtDNA-cGAS-STING pathway. Yet, the precise mechanism by which selenium antagonizes TMT-induced renal inflammation in chickens through ROS-mtDNA-cGAS-STING-mediated pyroptosis remains elusive. We generated a chicken TMT model (10 μg kg^-1 gavage) ± Se-enriched diet (2 mg kg^-1). Primary chicken embryo kidney (CEK) cells were used for in vitro validation. Both in vivo and in vitro data revealed that TMT suppressed antioxidants (CAT, GSH-Px, SOD, T-AOC), raised H₂O₂/MDA, and provoked excessive ROS. TMT also depolarized mitochondrial membrane potential (ΔΨm), elevated mitochondrial ROS (mtROS), induced mtDNA release, and disturbed mitochondrial dynamics, culminating in severe mitochondrial dysfunction. Cytoplasmic mtDNA activated the cGAS-STING pathway, up-regulating key signaling molecules and increasing pyroptosis markers (Caspase1, NLRP3, GSDMD, IL-18) and pro-inflammatory cytokines (TNF-α, ASC, IL-1β, IL-6). Se supplementation reversed these alterations. Importantly, the Se-mediated protection was abolished by the oxidative stress inducer sanguinarine, the cGAS-STING agonist STING-Agonist 12, or the pyroptosis activator nigericin. Collectively, our results demonstrate that Se alleviates TMT-induced renal pyroptosis and inflammation by reducing ROS, preserving mitochondrial homeostasis, preventing mtDNA leakage, and restraining the cGAS-STING pathway. These findings not only elucidate the molecular basis of TMT nephrotoxicity but also support Na₂SeO₃ as a candidate therapeutic for TMT-induced kidney injury.