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This retrospective clinical data showed that UFH has significant protective effects in sepsis compared to low\u2010molecular\u2010weight heparin and enoxaparin, indicating potential benefits of its non\u2010anticoagulant properties. Recombinant protein chip screening, surface plasmon resonance, and molecular docking data demonstrated that UFH specifically bound to the cytoplasmic Drp1 protein through its zone 2 non\u2010anticoagulant segment. In\u2010vitro experiments verified that UFH's specific binding to Drp1 suppressed Drp1 translocation to mitochondria following \u201csepsis\u201d challenge, thereby improving mitochondrial morphology, function and metabolism in vascular endothelial cells. Consequently, UHF comprehensively protected mitochondrial quality, thus reducing vascular leakage and improving prognosis in a sepsis rat model. 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