Resveratrol reduces ROS-induced ferroptosis by activating SIRT3 and compensating the GSH/GPX4 pathway

Molecular Medicine

Research Article

Yiwei Ren¹  Tianli Shen¹  Zijun Wang¹  Kai Deng¹  Enmeng Li¹  Gan Li¹  Xingjie Wang¹  Chao Qu¹  Xuejun Sun¹  Zhengdong Jiang¹  Xuqi Li²  Jie Lian³ 

[1] Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China;Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China;Department of Talent Highland, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China;Department of Pathology, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China;

关键词: Ischemia-reperfusion injury;    Ferroptosis;    SIRT3/FoxO3a pathway;    Resveratrol;    GSH/GPX4 pathway;   

DOI  :  10.1186/s10020-023-00730-6

 received in 2023-04-11, accepted in 2023-09-17,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundIntestinal ischemia-reperfusion injury occurs in acute intestinal obstruction, intussusception, acute mesenteric artery embolism, and other diseases and can lead to local intestinal necrosis, distant organ involvement, or systemic reactions, with high morbidity and mortality. Ferroptosis plays a crucial role in intestinal ischemia-reperfusion injury, and inhibition of ferroptosis may provide new approaches for treating the disease. SIRT3 protects cells from oxidative stress and may be involved in the process of ferroptosis. We hypothesized that resveratrol, an agonist of SIRT3, could ameliorate intestinal ischemia-reperfusion injury by compensating the GSH/GPX4 pathway.MethodsIntestinal ischemia-reperfusion (I/R) and Caco-2 hypoxia-reoxygenation models were established. Transmission electron microscopy was used to assess mitochondrial function; the Chiu’s score was used to evaluate the degree of intestinal mucosal injury based on HE staining; and Western blot was used to detect the SIRT3/FoxO3a pathway, tight junction proteins and ferroptosis-related protein expression. Sirt3-/- C57, shSIRT3-Caco-2 cells and siFoxO3a-Caco-2 cells were established. C11-BODIPY was used to detect lipid peroxide in cells; FD4 and IFABP were used to detect intestinal permeability; MitoSOX was used to detect ROS levels; and MitoTracker and immunofluorescence colocalization were used to detect SIRT3 levels.ResultsIn the intestinal I/R model, I/R injury occurs mainly during the reperfusion period and leads to ferroptosis through the GSH/GPX4 pathway. Resveratrol could reduce ferroptosis and ameliorate I/R injury by activating SIRT3. In Sirt3-/- mice, more intestinal mucosal cells underwent ferroptosis, I/R injury was more severe, and resveratrol lost the ability to ameliorate I/R injury. In addition, hypoxia-reoxygenation increased RSL3-induced ferroptosis sensitivity in Caco-2 cells in vitro. In the presence of shSIRT3 or RSL3 alone, resveratrol could ameliorate Caco-2 ferroptosis, but not RSL3-induced shSIRT3-Caco-2 ferroptosis. Furthermore, resveratrol might activate the SIRT3/FoxO3a pathway, increase the expression of SOD2 and catalase, and inhibit ROS generation, thus reducing lipid peroxidation and ferroptosis.ConclusionTo date, this is the first study to show that resveratrol ameliorates intestinal ischemia-reperfusion injury by activating SIRT3 and reducing ferroptosis. Resveratrol can reduce intestinal ischemia-reperfusion injury by activating the SIRT3/FoxO3a pathway, increasing the expression of SOD2 and catalase, reducing ROS and LPO production, compensating for the GSH/GPX4 pathway and inhibiting ferroptosis.Graphical abstractResveratrol increases the expression of SOD2 and catalase, reduces the production of ROS and LPO, compensates for the GSH/GPX4 pathway and inhibits ferroptosis by activating the SIRT3/FoxO3a pathway

【 授权许可】

CC BY   
© The Feinstein Institute for Medical Research 2023

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