Journal of inflammation research · 2026
KLF4 Protects Against Sepsis-Induced Coagulopathy via Inhibition of the AKT/mTOR/STAT3 Signaling Pathway.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Rongrong, Hong Yun, Hai Darong, Du Hongyan, Zhao Liwen, Li Zhengyan, Yin Fangkai, Zheng Wanli, Wang Kaicheng, Pan Jingye, Huang Yueyue
Аннотация
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.
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.