Polymyxin B Attenuates Sepsis-Induced Acute Kidney Injury by Activating a SUMO1-p65 "Molecular Brake" in Kidney Organoids.

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.