Synthetic anticoagulant octaparin targets mitochondrial cardiolipin-GSDMD axis to rescue redox homeostasis in sepsis
Shule Zhang, Cong Feng, Ning Yu, Rui Fang, Yingxin Zhang, Simeng Chen, Lijuan Cao, Jianfa Zhang
Abstract
Sepsis, characterized by dysregulated immune responses and mitochondrial dysfunction, currently has few effective therapies that directly target these cellular mechanisms, and conventional heparin and related analogues provide inadequate immunomodulatory benefits. Here, we investigated the synthetic heparin analogue octaparin, which exhibits enhanced anticoagulant safety, for its potential to mitigate sepsis by targeting mitochondrial and redox pathways. Using murine models of lipopolysaccharide (LPS)-induced endotoxemia and Salmonella typhimurium -induced sepsis, along with in vitro studies performed using murine bone marrow-derived macrophages (BMDMs) and the human acute monocytic leukemia THP-1 cell line, we demonstrate that octaparin significantly improves survival and attenuates multi-organ (lung, liver, kidney) damage. Octaparin outperformed heparin, enoxaparin, and fondaparinux in suppressing systemic inflammation including TNF-α, IL-6, IL-1β and bacterial burden. Transcriptomic analysis revealed octaparin reprograms macrophage immunometabolism, suppressing pro-inflammatory pathways while enhancing phagocytosis. Crucially, octaparin inhibited both canonical and non-canonical inflammasome activation, reduced generation of the pyroptotic executor GSDMD-N-terminal fragment (GSDMD-NT), and specifically diminished mitochondrial localization of GSDMD-NT by downregulating key cardiolipin synthesis and transport genes. Furthermore, octaparin uniquely reversed LPS-induced mitochondrial dysfunction. This restoration was accompanied by improvements in mitochondrial quality and the reestablishment of redox homeostasis. Collectively, octaparin confers multifaceted protection in sepsis, positioning it as a promising redox-targeted therapeutic for sepsis. • Octaparin outperforms heparin and related analogues in murine sepsis, improving survival, reducing multi-organ damage, inflammation and bacterial burden. • Octaparin reverses mitochondrial dysfunction and reprograms macrophage immunometabolism to enhance phagocytosis. • Octaparin dually inhibits inflammasomes, suppressing GSDMD-NT generation and its mitochondrial translocation through downregulation of cardiolipin biosynthesis.