Polymyxin B Attenuates Sepsis‐Induced Acute Kidney Injury by Activating a SUMO1‐p65 “Molecular Brake” in Kidney Organoids

ABSTRACT Sepsis‐induced acute kidney injury (SAKI) is a deadly complication in critical care, driven by a devastating inflammatory surge and loss of renal parenchymal integrity. While polymyxin B (PMB) is traditionally utilized as a last‐resort antibiotic, emerging evidence suggests it possesses non‐canonical immunomodulatory properties that remain mechanistically elusive. This study investigated the intracellular post‐translational modification (PTM) pathways through which PMB mitigates renal inflammation. We employed a dual‐model approach utilizing 3D mouse kidney organoids and SUMO1 −/− mouse models to examine the genetic dependency of PMB‐mediated renoprotection. Transcriptomic profiling revealed that PMB robustly suppresses NF‐κB ‐driven inflammatory programs in wild‐type (WT) organoids, specifically reducing the expression of Cxcl1 and Il6 . In contrast, this anti‐inflammatory efficacy was abrogated in SUMO1‐deficient models, where the pharmacological response shifted toward metabolic pathways, such as cholesterol metabolism. Mechanistically, PMB promotes SUMO1 conjugation to the NF‐κB p65 subunit, functioning as a “molecular brake” that limits p65 hyperphosphorylation and transcriptional activation. Together, these results identify the SUMO1‐p65 axis constitutes a pivotal regulatory checkpoint for PMB‐mediated immunomodulation. This study establishes a novel therapeutic paradigm by underscoring the promise of targeting PTM pathways to alleviate septic organ dysfunction.