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Our multicenter, cross-age cohort study identified insulin-like growth factor binding protein 6 (IGFBP6) as a critical regulator in sepsis diagnosis, prognosis, and mortality risk evaluation. Mechanistically, IGFBP6 engages in IGF-independent binding to prohibitin2 (PHB2) on epithelial cells, driving PHB2 tyrosine phosphorylation during sepsis. This process disrupts STAT1 phosphorylation, nuclear translocation, and its recruitment to the CCL2 promoter, ultimately impairing CCL2 transcription and macrophage chemotaxis. Crucially, PHB2 silencing via siPHB2 and STAT1 activation using 2-NP restored CCL2 expression in vitro and in vivo, improving bacterial clearance and survival in septic mice. Concurrently, IGFBP6 compromised macrophage bactericidal activity by inhibiting Akt phosphorylation, reducing ROS\/IL-1\u03b2 production and phagocytic capacity \u2014 defects reversible by Akt agonist SC79. Collectively, IGFBP6 emerges as an endogenous driver of sepsis pathogenesis, positioning it as a dual diagnostic biomarker and therapeutic target. Intervention strategies targeting IGFBP6-mediated signaling may offer transformative approaches for sepsis management.<\/jats:p>","DOI":"10.1172\/jci184721","type":"journal-article","created":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T19:01:03Z","timestamp":1762110063000},"source":"Crossref","is-referenced-by-count":6,"title":["IGFBP6 orchestrates antiinfective immune collapse in murine sepsis via prohibitin-2\u2013mediated immunosuppression"],"prefix":"10.1172","volume":"135","author":[{"given":"Kai","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, 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