<scp>SUMOylation</scp> of <scp>ZEB1</scp> Modulates <scp>PANoptosis</scp> in Burn‐Induced Early Acute Kidney Injury

Burn-induced acute kidney injury (AKI) involves inflammatory programmed cell death pathways, including PANoptosis. This study investigated how SUMOylation of the transcription factor ZEB1 regulates PANoptosis in early burn-induced AKI. Human AKI datasets were analyzed for ZEB1 expression and correlation with PANoptosis/SUMOylation genes. A rat burn-AKI model (24-72 h) evaluated renal dysfunction (creatinine, urea), histopathology (H&E, TUNEL) and oxidative stress (MDA/SOD/CAT). In vitro, HK-2 cells under hypoxia/reoxygenation (H/R) assessed ZEB1 and PANoptosis effectors (Caspase-3/MLKL/GSDMD). Co-immunoprecipitation assessed ZEB1 SUMOylation and ubiquitination. Flow cytometry measured intracellular reactive oxygen species (ROS) levels. ELISA quantified IL-1β and IL-6. Functional studies used ZEB1 knockdown, SUMOylation inhibition (2-D08) and SENP1 overexpression. Bioinformatic analysis revealed ZEB1 upregulation in human AKI correlating with PANoptosis/SUMOylation genes. Burn-AKI rats showed significant renal dysfunction, injury, oxidative stress (peak 48 h), increased ZEB1/PANoptosis effectors and enhanced ZEB1 SUMOylation (reduced ubiquitination). Similar findings were observed in H/R-treated HK-2 cells. SENP1 overexpression reversed these changes. ZEB1 knockdown or SUMOylation inhibition improved cell viability and suppressed oxidative stress, inflammation and PANoptosis effectors. H/R-induced ZEB1 SUMOylation is reversed by SENP1 or 2-D08. ZEB1 SUMOylation promotes PANoptosis in burn-induced AKI, representing a potential therapeutic target for early intervention.