Abstract

Ischemia-reperfusion induced acute kidney injury (IRI-AKI) progression involves dysregulated tubular cell death. Z-DNA-binding protein 1 (ZBP1) mediated PANoptosis is a newly discovered form of programmed cell death; however, its role and upstream regulation in IRI-AKI remain unclear. Both ZBP1 and stimulator of interferon genes (STING) are cytosolic innate immune sensors that not only mediate antiviral immunity but also play critical roles in sterile inflammation. Here, our results indicate that inhibition of STING protects against IRI-AKI through downregulation of ZBP1 activity. Mechanistically, STING activation promotes the nuclear translocation of signal transducer and activator of transcription 1 (STAT1), which directly binds to the ZBP1 promoter to upregulate its transcription. Additionally, interferon signaling and STING cooperatively promotes STAT1 activation, thereby aggravating ZBP1 mediated PANoptosis. These findings establish the STING–STAT1–ZBP1 axis as a critical pathogenic hub and highlight it as a promising therapeutic target for IRI-AKI. Graphical