Unfractionated Heparin Enhances Sepsis Prognosis Through Inhibiting Drp1‐Mediated Mitochondrial Quality Imbalance

Unfractionated heparin (UFH) is commonly used as an anticoagulant in sepsis treatment and has recently been found to have non‐anticoagulant effects, but underlying mechanisms remain unclear. This retrospective clinical data showed that UFH has significant protective effects in sepsis compared to low‐molecular‐weight heparin and enoxaparin, indicating potential benefits of its non‐anticoagulant 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‐anticoagulant segment. In‐vitro experiments verified that UFH's specific binding to Drp1 suppressed Drp1 translocation to mitochondria following “sepsis” 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. These findings highlight the potential of UFH as a sepsis treatment strategy targeting non‐anticoagulation mechanism. This study demonstrates that heparin (UFH) treats sepsis by non‐anticoagulant mechanisms, targeting Drp1 to enhance mitochondrial quality and reduce vascular leakage. Through clinical database analysis and experimental validation, UFH's Zone 2 specifically binds Drp1, inhibiting its mitochondrial activity and stabilizing endothelial function, providing a novel target for future heparin derivatives in sepsis management and critical care.