Ochratoxin A induces lung cell PANoptosis through activation of the AIM 2 inflammasome

Ochratoxin A (OTA), a mycotoxin from filamentous fungi, significantly threatens human and animal health through food contamination. OTA is prevalent in food products, posing a significant health risk. Here, we observed that OTA induces senescence in lung cells. This study further assessed the toxicological effects of OTA on lung cells and clarified its molecular mechanism. We utilized in vitro cell models (TC-1 and MLE-12) to evaluate the impact of OTA on lung cells using Western-blot, indirect immunofluorescence and ELISA. The results revealed that OTA leads to inflammatory cell death in lung cells. Further investigations demonstrated that OTA elevates the expression levels of PANoptosis markers, including ZBP1, Caspase1/GSDMD (pyroptosis), Caspase3/7 (apoptosis) and RIP3/pMLKL (necroptosis). We further explored the mechanism through which OTA induces PANoptosis in lung cells. Experimental results indicated that OTA increased mitochondrial ROS levels, subsequently leading to a decrease in mitochondrial membrane potential, which activates AIM2. Consequently, AIM2 participates in the formation of ZBP1-induced PAN-optosome, ultimately resulting in PANoptosis of lung cells. In vivo studies further revealed that OTA induces lung damage. This new discovery establishes a basis for future studies on the toxicological effects of OTA on lung tissue.