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Obacunone inhibits RIPK1/RIPK3/MLKL-mediated necroptosis by suppressing mitochondrial ROS and MIF signaling in

Xiao-Yao Li1, Jing-Yuan Xie1, Yu-Tong Yin1

  • 1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

International Immunopharmacology
|November 29, 2025
PubMed
Abstract

Insights

Obacunone (OBA) protects against intestinal ischemia-reperfusion (IIR) injury by reducing cell death and inflammation. This natural compound shows promise as a therapeutic strategy for IIR and related disorders.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Pharmacology

Background:

  • Intestinal ischemia-reperfusion (IIR) causes significant damage, leading to high mortality.
  • Current treatments for IIR are limited, necessitating novel therapeutic approaches.
  • Obacunone (OBA), a natural limonoid, possesses known antioxidant and anti-inflammatory properties.

Purpose of the Study:

  • To investigate the protective effects of Obacunone (OBA) against intestinal ischemia-reperfusion (IIR) injury.
  • To elucidate the underlying mechanisms of OBA's action in IIR models.
  • To evaluate OBA as a potential therapeutic agent for IIR.

Main Methods:

  • Established in vivo (mouse) and in vitro (IEC-6 cells) models of IIR and oxygen-glucose deprivation/reoxygenation (OGD/R).
  • Assessed tissue damage, necroptosis markers (RIPK1, RIPK3, MLKL), mitochondrial function, and reactive oxygen species (ROS) production.
  • Utilized network pharmacology, molecular docking, and pharmacological validation involving MIF inhibition and recombinant MIF.

Main Results:

  • OBA pre-treatment significantly reduced IIR-induced intestinal damage and restored epithelial integrity.
  • OBA suppressed necroptosis by attenuating ROS accumulation, particularly mitochondrial ROS (mtROS), and preserving mitochondrial function.
  • Network pharmacology identified macrophage migration inhibitory factor (MIF) as a key target; OBA's effects were mediated via dual regulation of mtROS and MIF signaling.

Conclusions:

  • Obacunone (OBA) demonstrates significant protective effects against intestinal ischemia-reperfusion (IIR) injury.
  • OBA mitigates IIR damage by modulating mtROS and MIF-driven necroptosis pathways.
  • OBA represents a promising therapeutic candidate for treating IIR and associated inflammatory conditions.
Keywords:
Intestinal ischemia-reperfusion injuryMIFNecroptosisNetwork pharmacologyObacunonemtROS

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