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While polymyxin B (PMB) is traditionally utilized as a last\u2010resort antibiotic, emerging evidence suggests it possesses non\u2010canonical immunomodulatory properties that remain mechanistically elusive. This study investigated the intracellular post\u2010translational modification (PTM) pathways through which PMB mitigates renal inflammation. We employed a dual\u2010model approach utilizing 3D mouse kidney organoids and SUMO1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mouse models to examine the genetic dependency of PMB\u2010mediated renoprotection. Transcriptomic profiling revealed that PMB robustly suppresses NF\u2010\u03baB \u2010driven inflammatory programs in wild\u2010type (WT) organoids, specifically reducing the expression of\n                    <jats:italic>Cxcl1<\/jats:italic>\n                    and\n                    <jats:italic>Il6<\/jats:italic>\n                    . In contrast, this anti\u2010inflammatory efficacy was abrogated in SUMO1\u2010deficient models, where the pharmacological response shifted toward metabolic pathways, such as cholesterol metabolism. Mechanistically, PMB promotes SUMO1 conjugation to the NF\u2010\u03baB p65 subunit, functioning as a \u201cmolecular brake\u201d that limits p65 hyperphosphorylation and transcriptional activation. Together, these results identify the SUMO1\u2010p65 axis constitutes a pivotal regulatory checkpoint for PMB\u2010mediated immunomodulation. This study establishes a novel therapeutic paradigm by underscoring the promise of targeting PTM pathways to alleviate septic organ dysfunction.\n                  <\/jats:p>","DOI":"10.1002\/cbin.70209","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:53:50Z","timestamp":1790596430000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Polymyxin B Attenuates Sepsis\u2010Induced Acute Kidney Injury by Activating a SUMO1\u2010p65 \u201cMolecular Brake\u201d in Kidney Organoids"],"prefix":"10.1002","volume":"50","author":[{"given":"Qing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit Tianjin Fifth Central Hospital Tianjin China"},{"name":"Department of Emergency Medicine Tianjin Fifth Central Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4520-4122","authenticated-orcid":false,"given":"Na","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit Tianjin Fifth Central Hospital Tianjin China"},{"name":"Tianjin Key Laboratory of Epigenetics for Organ Development of Preterm Infants Tianjin Fifth Central Hospital Tianjin China"},{"name":"Emergency Medicine Research Institute, Tianjin Fifth Central Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Yu","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Epigenetics for Organ Development of Preterm Infants Tianjin Fifth Central Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3175-3112","authenticated-orcid":false,"given":"Yanxia","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Epigenetics for Organ Development of Preterm Infants Tianjin Fifth Central Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5147-1297","authenticated-orcid":false,"given":"Xiyun","family":"Bian","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Epigenetics for Organ Development of Preterm Infants Tianjin Fifth Central Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5762-2087","authenticated-orcid":false,"given":"Xiaoming","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit Tianjin Fifth Central Hospital Tianjin China"},{"name":"Emergency Medicine Research Institute, Tianjin Fifth Central Hospital Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Tianjin Fifth Central Hospital Tianjin China"},{"name":"Emergency Medicine Research Institute, Tianjin Fifth Central Hospital Tianjin China"},{"name":"School of Medicine Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingguo","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit Tianjin Fifth Central Hospital Tianjin China"},{"name":"Emergency Medicine Research Institute, Tianjin Fifth Central Hospital Tianjin China"},{"name":"School of Medicine Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.09.001"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","unstructured":"Bellomo R. 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