Scientists uncover a hidden protein driver of sepsis-related organ failure

Sepsis remains one of the most feared conditions in modern medicine, a runaway inflammatory response to infection that can shut down the kidneys, liver, and lungs in rapid succession. Despite decades of research, antibiotics, fluid resuscitation, and organ support have delivered only modest improvements in survival, and mortality from sepsis-associated multiple organ dysfunction syndrome remains stubbornly high. Now, a team of researchers reporting in the Journal of Advanced Research has identified a surprising molecular culprit: insulin-like growth factor-binding protein 7, or IGFBP7, a secreted protein long known as a biomarker of kidney injury that turns out to be far more than a passive bystander. According to the study, IGFBP7 actively drives organ damage during sepsis by hijacking a key mitochondrial enzyme and flooding tissues with a metabolite called succinate.

The investigation began in the clinic. The researchers measured serum IGFBP7 levels in patients with sepsis admitted to the Second Affiliated Hospital of Anhui Medical University and compared them with healthy controls. The results were striking: patients with sepsis showed markedly elevated circulating IGFBP7, and those levels correlated positively with serum creatinine, blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase, the standard laboratory markers of kidney and liver dysfunction. In other words, the more IGFBP7 a patient carried in their bloodstream, the worse their organs appeared to be faring. This clinical signal set the stage for a deeper mechanistic dive using animal models.

Turning to mice, the team used the cecal ligation and puncture model, a widely used experimental simulation of septic shock in which the cecum is perforated to release fecal bacteria into the abdominal cavity. As in humans, IGFBP7 surged in the serum and urine of septic mice, and Western blot analysis revealed upregulation of the protein in the kidneys, liver, and lungs. Immunofluorescence staining pinpointed the cellular sources: proximal tubular epithelial cells in the kidney and hepatocytes in the liver. Cultured mouse tubular epithelial cells and hepatocytes exposed to lipopolysaccharide, the toxic component of bacterial outer membranes, likewise ramped up IGFBP7 production, confirming that the response is cell-autonomous rather than a secondary artifact of systemic illness.

The decisive experiment came from genetics. The researchers generated mice lacking the Igfbp7 gene entirely, as well as organ-specific knockout lines in which the gene was deleted only in renal tubular epithelial cells or only in hepatocytes. When subjected to sepsis, the global knockout mice survived at significantly higher rates than their wild-type littermates. Their kidneys, livers, and lungs showed dramatically less injury: lower creatinine and BUN, reduced liver enzymes, less alveolar septal thickening and capillary congestion in the lungs, and blunted activation of NF-κB, the master transcriptional switch of inflammation. Proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 were all substantially tamped down. The tissue-specific knockouts confirmed that IGFBP7 acts locally within each organ, not merely as a circulating signal.

To understand how a secreted binding protein could wreak such havoc inside cells, the team performed an unbiased proteomic hunt. Using co-immunoprecipitation followed by liquid chromatography-tandem mass spectrometry, they pulled down proteins that physically associate with IGFBP7 in septic kidney tissue. The top candidate was oxoglutarate dehydrogenase, or OGDH, a critical enzyme in the tricarboxylic acid cycle that catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA, a direct precursor of succinate. The interaction was confirmed in the kidneys, liver, and lungs of septic mice, and high-resolution confocal microscopy showed IGFBP7 and OGDH co-localizing inside stressed cells. Subcellular fractionation revealed that IGFBP7, though classically considered a secreted protein, can be internalized by cells and detected in the mitochondrial fraction where OGDH resides. Molecular docking and truncation experiments mapped the binding interface to the Kazal-like and immunoglobulin-like C2-type domains of IGFBP7.

The functional consequences of this interaction proved to be a story about a chemical modification called lysine succinylation. Succinyl-CoA can covalently attach succinate groups to lysine residues on target proteins, altering their conformation and activity, and the mitochondrial enzyme SIRT5 normally acts as a desuccinylase that keeps this modification in check. The researchers found that during sepsis, the association between OGDH and SIRT5 was weakened, and IGFBP7 overexpression further disrupted this partnership. The result was a marked increase in overall OGDH succinylation, which coincided with enhanced OGDH enzymatic activity and a flood of succinate in the serum and kidney tissue. Consistent with this chain of events, serum succinate levels in mice correlated positively with IGFBP7, creatinine, ALT, and interleukin-1 beta, tying the metabolic shift directly to organ injury and inflammation.

Causality was tested in both directions. First, the team showed that succinyl phosphonate, a specific inhibitor of OGDH, reduced the expression of the kidney injury marker KIM-1 and NF-κB phosphorylation in stressed cells, implicating OGDH activity in the damage pathway. Second, and more compellingly, they administered dimethyl succinate, a cell-permeable succinate ester, to Igfbp7 knockout mice undergoing sepsis. Restoring succinate levels largely erased the protective phenotype: kidney and liver function markers climbed, tubular injury and macrophage infiltration worsened, and lung dysfunction partially returned. A parallel rescue in cultured cells produced the same outcome. Together, these experiments establish succinate accumulation as a critical downstream mediator through which IGFBP7 inflicts its damage.

The downstream target of all this succinate is the mitochondrion itself. Excessive succinate is known to disrupt redox balance, drive reactive oxygen species production through complex II of the electron transport chain, and destabilize HIF-1 alpha to amplify interleukin-1 beta expression. In this study, lipopolysaccharide-treated cells with high IGFBP7 showed depressed oxygen consumption, depleted ATP, reduced mitochondrial DNA copy number, fragmented and rounded mitochondria, collapsed membrane potential, and oxidative stress. Silencing Igfbp7 reversed essentially all of these defects, restoring elongated mitochondrial networks, membrane potential, and energy production. In septic mice, Igfbp7 deficiency preserved mitochondrial ultrastructure as visualized by transmission electron microscopy, rebalanced fission and fusion protein expression, and reduced oxidative damage markers across the kidneys, liver, and lungs.

Perhaps the most clinically exciting finding is that the damage is pharmacologically reversible. A neutralizing antibody against IGFBP7, administered immediately after sepsis induction and again twelve hours later, lowered circulating IGFBP7 and succinate, reduced inflammatory cytokines, and significantly improved kidney, liver, and lung function in septic mice. Tissue histology showed less injury and fewer infiltrating macrophages in all three organs, and mitochondrial dynamics and biogenesis markers in the kidney normalized. The treatment also attenuated senescence-associated changes, reducing p16 and p21 expression and senescence-associated beta-galactosidase activity in renal tissue, consistent with IGFBP7’s established role as a component of the senescence-associated secretory phenotype.

The authors are careful to note the limitations. The evidence rests primarily on young male mice and a small clinical cohort, the cecal ligation and puncture model cannot fully capture the heterogeneity of human sepsis, and the precise lysine residues on OGDH whose succinylation drives its hyperactivity remain unidentified. How IGFBP7 enters cells and reaches the mitochondrial compartment is also unresolved. Still, the study delivers a coherent and testable model: sepsis elevates IGFBP7, which penetrates cells and displaces SIRT5 from OGDH, unleashing succinate production that poisons mitochondria and ignites inflammatory injury across multiple organs. With IGFBP7 inhibitors already under investigation for kidney disease and fibrosis, the prospect of translating this axis into a therapy for sepsis-induced multiple organ dysfunction no longer seems remote, and a protein once regarded as a mere biomarker may soon become a treatment target in one of medicine’s most urgent battles.

Subject of Research: The role of IGFBP7 and OGDH-mediated succinate accumulation in sepsis-induced multiple organ dysfunction

Article Title: IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation

Article References: Xie, S.-S., Dong, Y.-H., Xu, L., Dong, Z.-H., Gao, Y.-Y., Li, W., Ma, W.-X., Ru, Y.-X., Zhao, T., Hou, R., Zhang, L.-X., Yang, Q., Jin, J., Wen, J.-G., & Meng, X.-M. (2026). IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.09.013

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.09.013

Keywords: sepsis, IGFBP7, OGDH, succinate, mitochondrial dysfunction, multiple organ dysfunction syndrome, SIRT5, succinylation, inflammation, NF-kB, acute kidney injury, therapeutic target