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

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, 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. RESULTS: In 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. CONCLUSION: To 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. Resveratrol 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.

Ficus hirta Vahl. ameliorates liver fibrosis by triggering hepatic stellate cell ferroptosis through GSH/GPX4 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ficus hirta Vahl., a traditional Chinese medicine commonly used in the Lingnan region, has been extensively used for liver disease treatment in China. Its notable antioxidant and anti-inflammatory properties have been reported in previous studies. However, its potential effect and underlying mechanism on liver fibrosis remains unclear. AIM OF STUDY: This study was aimed to investigate the effect and its underlying mechanism of Ficus hirta Vahl on liver fibrosis in vitro and in vivo. MATERIALS AND METHODS: The main components of Ficus hirta Vahl in blood were investigated by using UPLC-Q/TOF-MS/MS. Two animal models of liver fibrosis, the CCl4 and MCD induced mice, were used to assess the efficacy of Ficus hirta Vahl on liver fibrosis. Metabolomics was used to detect the level of metabolites in the serum of liver fibrosis mice after Ficus hirta Vahl treatment. Furthermore, the mechanism was validated in vitro using the human liver stellate cell line LX-2. The binding affinities of the active ingredients of Ficus hirta Vahl to the main targets of liver fibrosis were also determined. Finally, we identified the key active ingredients responsible for the treatment of liver fibrosis in vivo. RESULTS: Fibrosis and inflammatory markers were significant down-regulation in both CCl4 and MCD induced liver fibrosis mice after Ficus hirta Vahl administration in a dose-dependent manner. We found that Ficus hirta Vahl may primarily exert its effect on liver fibrosis through the glutathione metabolic pathway. Importantly, the glutathione metabolic pathway is closely associated with ferroptosis, and our subsequent in vitro experiments provided evidence supporting this association. Ficus hirta Vahl was found to modulate the GSH/GPX4 pathway, ultimately leading to the amelioration of liver fibrosis. Moreover, using serum pharmacochemistry and molecular docking, we successfully identified apigenin as a probable efficacious monomer for the management of liver fibrosis and subsequently validated its efficacy in mice with CCl4-induced hepatic fibrosis. CONCLUSION: Ficus hirta Vahl triggered the ferroptosis of hepatic stellate cell by regulating the GSH/GPX4 pathway, thereby alleviating liver fibrosis in mice. Moreover, apigenin is a key compound in Ficus hirta Vahl responsible for the effective treatment of liver fibrosis.

The emerging role of ferroptosis in female reproductive disorders.

Iron, as an essential trace element for the organism, is vital for maintaining the organism's health. Excessive iron can promote reactive oxygen species (ROS) accumulation, thus damaging cells and tissues. Ferroptosis is a novel form of programmed cell death distinguished by iron overload and lipid peroxidation, which is unique from autophagy, apoptosis and necrosis, more and more studies are focusing on ferroptosis. Recent evidence suggests that ferroptosis is associated with the development of female reproductive disorders (FRDs), including polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), endometriosis (EMs), ovarian cancer (OC), preeclampsia (PE) and spontaneous abortion (SA). Pathways and genes associated with ferroptosis may participate in processes that regulate granulosa cell proliferation and secretion, oocyte development, ovarian reserve function, early embryonic development and placental oxidative stress. However, its exact mechanism has not been fully revealed. Therefore, our review systematically elaborates the occurrence mechanism of ferroptosis and its research progress in the development of FRDs, with a view to providing literature references for clinical targeting of ferroptosis -related pathways and regulatory factors for the management of FRDs.

The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review.

Background and Objective: Ferroptosis is a recently discovered form of cell death which differs from other forms of cell death in terms of morphology, biochemistry, and regulatory mechanisms. Ferroptosis is regulated by a complex system and the precise molecular mechanisms are still being elucidated. Over the past few years, extensive research has revealed that the essence of ferroptosis is iron-dependent accumulation of lipid hydroperoxides induced by oxidative stress, and the System Xc-glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway is the main ferroptosis prevention system. Meanwhile, other antioxidant systems have also been implicated in regulating ferroptosis, including the transsulfuration pathway, mevalonate pathway, ferroptosis inhibitory protein 1 (FSP1)-Coenzyme Q10 (CoQ10) pathway, dihydroorotate dehydrogenase (DHODH)-dihydroubiquione (CoQH2) pathway, and GTP cyclohydrolase-1 (GCH1)-tetrahydrobiopterin (BH4) pathway. This article reviews the molecular mechanisms of ferroptosis and its critical role in antioxidant systems, aiming to reveal that antioxidation is an important method of inhibiting ferroptosis and to provide a new direction for the treatment of ferroptosis-related diseases. Methods: We searched all original papers and reviews about the molecular mechanisms of ferroptosis in antioxidant systems using PubMed to November 2021. The search terms used included: 'ferroptosis', 'ferroptosis inducers', 'ferroptosis inhibitors', 'ferroptosis and GSH', 'ferroptosis and GPX4', 'ferroptosis and System Xc-', 'SLC7A11', 'P53', 'NRF2 and ferroptosis', 'iron metabolism', 'lipid peroxidation', 'antioxidant systems', 'transsulfuration pathway', 'mevalonate pathway', 'FSP1-CoQ10', 'DHODH-CoQH2', and 'GCH1-BH4'. Key Content and Findings: We first introduced the origin of ferroptosis and its common inhibitors and inducers. Next, we discussed the molecular mechanisms of ferroptosis and its role in antioxidant systems in existing studies. Finally, we briefly summarized the relationship between ferroptosis and diseases. It reveals that antioxidation is an important method of inhibiting ferroptosis. Conclusions: This review discusses the recent rapid progress in the understanding of the molecular mechanisms of ferroptosis and its role in several antioxidant systems.