IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation.

INTRODUCTION: Sepsis is a life-threatening systemic inflammatory syndrome frequently complicated by multiple organ dysfunction, yet the molecular mechanisms driving organ failure during sepsis remain poorly understood. Insulin-like growth factor-binding protein 7 (IGFBP7) has been implicated in various organ diseases; however, its role in sepsis-induced multiple organ dysfunction remains unclear. OBJECTIVES: This study aimed to determine whether IGFBP7 contributes to the pathogenesis of sepsis-induced multiple organ dysfunction and to elucidate the underlying mechanisms. METHODS: Circulating IGFBP7 levels were measured in patients and mice with sepsis. Global and organ-specific Igfbp7 knockout mice were used to evaluate the role of IGFBP7 in cecal ligation and puncture (CLP)-induced sepsis. Liquid chromatography-tandem mass spectrometry was used to investigate the downstream mechanisms. RESULTS: Serum IGFBP7 levels were markedly elevated in patients with sepsis and positively correlated with indices of organ dysfunction. IGFBP7 expression was also increased in the circulation and multiple organs of septic mice. Global or organ-specific deletion of Igfbp7 significantly alleviated CLP-induced multiple organ injury and inflammatory responses. Mechanistically, IGFBP7 interacted with 2-oxoglutarate dehydrogenase (OGDH) and was associated with reduced OGDH-sirtuin 5 association, increased overall OGDH succinylation, enhanced OGDH activity, and excessive succinate accumulation. Succinate accumulation disrupted mitochondrial homeostasis, promoted oxidative stress, and amplified proinflammatory responses. Importantly, anti-IGFBP7 treatment restored mitochondrial integrity, improved organ function, and reduced systemic inflammation. CONCLUSION: These findings identify IGFBP7 as a critical metabolic regulator in sepsis and highlight an IGFBP7-OGDH-succinate axis that contributes to mitochondrial dysfunction and inflammatory injury. Targeting IGFBP7 may represent a potential therapeutic strategy for sepsis-induced multiple organ dysfunction.