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

作者：Xingjie Wang, Tianli Shen, Jie Lian, Kai Deng, Chao Qu, Enmeng Li, Li Gan, Yiwei Ren, Zijun Wang, Zhengdong Jiang, Xuejun Sun, Xuqi Li · 发表于：Molecular Medicine · 年份：2023 · DOI：10.1186/s10020-023-00730-6 · 被引用次数：147 · 研究领域：Cancer-related molecular mechanisms research、Ferroptosis and cancer prognosis、Heme Oxygenase-1 and Carbon Monoxide

Abstract Background Intestinal 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. Methods Intestinal 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, sh SIRT3 -Caco-2 cells and si FoxO3a -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. Results In the intestinal I/R model, I/R injury occurs mainly duri...