ArticleJournal of inflammation research2026
KLF4 Protects Against Sepsis-Induced Coagulopathy via Inhibition of the AKT/mTOR/STAT3 Signaling Pathway.
Article in Journal of inflammation research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: Coagulation dysfunction is an independent predictor of morbidity and mortality in patients with severe sepsis, yet current therapeutic options remain inadequate. This study systematically evaluated the therapeutic potential of Krüppel-like factor 4 (KLF4) in sepsis-induced coagulopathy and explored the underlying molecular mechanisms. Methods: In vivo, mice were randomized into sham operation group, cecal ligation and puncture (CLP) group, and CLP + APTO-253 groups. The KLF4 agonist APTO-253 was intraperitoneally administered to CLP-induced septic mice to evaluate systemic inflammation, coagulation dysfunction, acute lung injury, and survival outcomes. In vitro, RAW264.7 macrophages were assigned to six core treatment groups: control group, APTO-253 group, LPS group, LPS + APTO-253 group, LPS + KLF4 overexpression group, and LPS + KLF4 knockdown group. Cellular inflammatory responses, coagulation-related biomarkers, and AKT/mTOR/STAT3 pathway activity were detected. Results: In vivo, APTO-253 treatment significantly attenuated systemic inflammation and coagulopathy in septic mice via the upregulation of KLF4, accompanied by reduced levels of proinflammatory cytokines (interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α)) and coagulation-related biomarkers (fibrinogen, thrombin-antithrombin complex (TAT), D-dimer, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1)). This therapeutic intervention ameliorated pathological manifestations, including pulmonary tissue damage, macrophage infiltration, and fibrin deposition, ultimately enhancing survival. In vitro, both APTO-253 treatment and KLF4 overexpression suppressed LPS-induced IL-6, IL-1β, TNF-α, TF, and PAI-1 through the inhibition of the AKT/mTOR/STAT3 signaling pathway. Conversely, KLF4 knockdown potentiated LPS-induced hyperactivation of this pathway, resulting in amplified proinflammatory and procoagulant responses. Conclusion: KLF4 overexpression ameliorates sepsis-induced coagulation dysfunction by inhibiting AKT/mTOR/STAT3 signaling. Thus, KLF4 represents a potential therapeutic target for coagulopathy in sepsis.
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