OGDH primes macrophage for M1-like polarization and ferroptosis in sepsis associated acute lung injury

BACKGROUND: Sepsis-associated acute lung injury (S-ALI) is a clinical syndrome characterized by dysregulated inflammation and overwhelming oxidative stress, and is associated with a poor prognosis. Alpha-ketoglutarate dehydrogenase (OGDH) is a key enzyme in the tricarboxylic acid cycle that catalyzes the oxidative decarboxylation of α-ketoglutarate (α-KG) to succinyl-CoA, a critical step linking mitochondrial energy metabolism to immune response. However, the mechanism by which OGDH participates in S-ALI remains unclear. METHODS: The mouse model of sepsis was established via intraperitoneal injection of lipopolysaccharide (LPS), and CPI-613 was administered intraperitoneally prior to LPS challenge. Peripheral blood samples and baseline characteristics were collected from septic patients. In vitro, BMDMs were used to evaluate the therapeutic effects of CPI-613. Using untargeted metabolomics (LC-MS), RNA sequencing transcriptomics (RNA-seq), macrophage-specific small interfering Nrf2 RNA (si-Nrf2), and enzyme-linked immunosorbent assay (ELISA), we assessed lung tissue pathology, inflammatory cytokine levels, ferroptosis markers, OGDH enzyme activity, and clinical correlation. RESULTS: In LPS-induced septic mice, we observed systemic metabolic changes characterized by decreased α-KG levels and increased OGDH enzyme activity. Intraperitoneal administration of the OGDH inhibitor CPI-613 attenuated acute lung injury and systemic inflammation, thereby improving survival. Flow cytometry revealed that CPI-613 suppressed M1-like polarization of alveolar macrophages in septic mice, a finding corroborated in vitro. Transcriptomic profiling indicated that CPI-613 treatment preferentially modulated ferroptosis and glutathione metabolic pathways in LPS-treated bone marrow-derived macrophages (BMDMs). In both LPS-challenged mice and BMDMs, CPI-613 reduced ferroptosis biomarkers and activated the Nrf2-mediated antioxidant axis. Critically, genetic silencing of Nrf2 via siRNA or pharmacological inhibition with ML385 eliminated the anti-ferroptotic effects of CPI-613, positioning Nrf2 as a central mediator of this protection. Serum from patients with sepsis-associated ARDS exhibited significantly elevated OGDH enzyme activity relative to healthy controls. Moreover, OGDH activity correlated strongly with disease severity and clinical outcomes, including septic shock and death. CONCLUSION: Overall, our study reveals that OGDH is a key immunometabolism regulator and a novel biomarker in S-ALI, and its inhibitor CPI-613 may represent a potential therapeutic target for this condition.