Dendrobine alleviates lung injury in septic mice by inhibiting mitochondrial-endoplasmic reticulum crosstalk-mediated NLRP3 inflammasome activation

  • J Pharmacol Sci. 2026 Aug;161(4):119-129. doi: 10.1016/j.jphs.2026.05.007.
Shichao Zhang  1 ,  Kaihang Luo  1 ,  Xinyue Wei  2 ,  Cheng Qing  3 ,  Jianguo Zhang  4 ,  Huazhang Wei  5 ,  Yongan Yan  5 ,  Yuting Yang  3 ,  Zhenguo Zeng  6 ,  Shuying Huang  7
Affiliations
  • 1. Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, China; Jiangxi Institute of Respiratory Disease, Nanchang, 330006, China.
  • 2. School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, China.
  • 3. Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, China.
  • 4. Department of Critical Care Medicine, Linyi People's Hospital, Linyi, Shandong, China.
  • 5. Department of Critical Care Medicine, The Affiliated Hospital of Jinggangshan University, Ji'an, 343000, China.
  • 6. Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, China. Electronic address: [email protected].
  • 7. Department of Reproductive Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie, Nanchang, 330000, China. Electronic address: [email protected].
PMID: 42303347 DOI: 10.1016/j.jphs.2026.05.007
Abstract

Sepsis, a life-threatening disorder driven by a dysregulated host response to Infection, is frequently accompanied by acute lung injury (ALI), worsening disease severity, and mortality. Excessive macrophage-mediated inflammation is central to its pathogenesis. Given emerging evidence that mitochondria-endoplasmic reticulum (ER) crosstalk drives inflammatory injury, we investigated whether modulating this interaction could mitigate sepsis-induced damage. Using LPS-stimulated THP-1 macrophages and a murine model of LPS-induced sepsis, we evaluated the anti-inflammatory and organ-protective effects of dendrobine, a bioactive alkaloid from Dendrobium nobile Lindl. Dendrobine suppressed glycolysis-induced mitochondria-ER crosstalk, thereby reducing macrophage-driven inflammation and tissue injury. In vivo, dendrobine lowered circulating interleukin (IL)-1β and IL-18 levels and alleviated ALI. Mechanistically, dendrobine decreased Reactive Oxygen Species production and mitochondrial DNA (mtDNA) release, leading to downregulation of NLRP3 and cleaved Caspase-1. These effects stemmed from inhibition of hypoxia-inducible factor-1α (HIF-1α) and Hexokinase 2 (HK2)-mediated glycolysis, preventing HK2 dissociation from voltage-dependent anion channel 1 (VDAC1) and disrupting IP3R-GRP75-VDAC1 complex formation. Collectively, these findings demonstrate that dendrobine protects against sepsis-induced organ injury by targeting the IP3R-GRP75-VDAC1-HK2 axis in macrophages, highlighting its therapeutic potential for sepsis.

Keywords
Acute lung injury(ALI); Dendrobine; Hexokinase2(HK2); Mitochondria-associated endoplasmic reticulum membrane (MAMs); Sepsis.
Products