Citrinin induces renal PANoptosis by mediating mitochondrial dysfunction through the GSDMD-N/DRP1 pathway.

Citrinin (CTN), a nephrotoxic mycotoxin with high environmental stability, is widely present in contaminated food sources, leading to chronic ingestion in humans and animals. Although CTN exposure is closely associated with Balkan endemic nephropathy (BEN), the molecular mechanisms underlying CTN-induced renal injury remain largely elusive. PANoptosis-a newly recognized form of regulated cell death that integrates pyroptosis, apoptosis, and necroptosis-has emerged as a key contributor to kidney pathology. In this study, we established both in vivo (KM mice) and in vitro (TCMK-1 cells) models of CTN exposure and observed concurrent activation of pyroptotic, apoptotic, and necroptotic pathways, indicating PANoptosis induction. Furthermore, CTN treatment triggered mitochondrial structural damage accompanied by DRP1 upregulation, consequently leading to elevated mitochondrial ROS generation and cytochrome c release. To clarify the role of mitochondrial dysfunction in PANoptosis, we used the DRP1 inhibitor Mdivi-1, which restored mitochondrial integrity, alleviated dysfunction, and significantly reduced CTN-induced apoptotic and necroptotic cell death. Furthermore, mtROS and cytochrome c were identified as essential mediators of necroptosis and apoptosis, respectively, as shown by treatment with Mito-TEMPO and BALI. Notably, disulfiram, a GSDMD-N inhibitor, also mitigated mitochondrial dysfunction and PANoptotic responses through the DRP1 pathway. Molecular docking and Co-IP assays confirmed a direct interaction between GSDMD-N and DRP1. Collectively, these findings reveal that CTN induces PANoptosis through GSDMD-N/DRP1-mediated mitochondrial dysfunction, offering new mechanistic insights into CTN-induced nephrotoxicity and highlighting potential therapeutic targets for mitigating mycotoxin-associated kidney injury.