Gingerenone A Alleviates Ferroptosis in Secondary Liver Injury in Colitis Mice via Activating Nrf2–Gpx4 Signaling Pathway

Abstract

Patients with ulcerative colitis (UC) have been found to be frequently associated with secondary liver injury (SLI). In this study, we investigated the protective effect of GA on dextran sodium sulfate (DSS)-induced SLI in mice and its mechanism. The SLI was established by adding 4% DSS in the drinking water of mice, and the effects of GA (5, 20 mg/kg, p.o., once a day for 7 days) in hepatic tissues were analyzed. HepG2 cells were induced by lipopolysaccharide (LPS) to detect the effect of GA on ferroptosis and the underlying mechanism. Pathological damage was determined by H&E. Liver parameters (AST and ALT), antioxidant enzyme activities (MDA and SOD), and the level of Fe2+ in the liver were detected by kits. Cytokine levels (TNF-α, IL-1β, and IL-6) and Gpx4 activity in the liver were detected by ELISA. Finally, the activation of nuclear factor erythroid 2-like 2 (Nrf2) was detected to explore the mechanism. The results indicated that GA significantly attenuated DSS-induced hepatic pathological damage, liver parameters, and cytokine levels and increased the antioxidant enzyme activities. Moreover, GA attenuated ferroptosis in DSS-induced liver injury and upregulated Gpx4 expression in DSS-induced mice. Mechanistic experiments revealed that GA activated Nrf2 in mice. Taken together, this study demonstrates that GA can alleviate ferroptosis in SLI in DSS-induced colitis mice, and its protective effects are associated with activating the Nrf2–Gpx4 signaling pathway.

Ginsenoside Rg1 Alleviates Ulcerative Colitis in Obese Mice by Regulating the Gut Microbiota–Lipid Metabolism–Th1/Th2/Th17 Cells Axis

“…In addition, liver malfunction is a common pathology in obesity and UC. 52,53 We found that the levels of AST and ALT in the serum of obese mice with colitis were higher than those of obese mice alone. Interestingly, G-Rg1, a compound we investigated, has been reported to improve lipid metabolism and liver function.…”

Syringic Acid Alleviates Dextran Sulfate Sodium-Induced Colitis in Mice by Modulating Gut Microbiota

“…59 Additionally, the presence of a leaky gut may exacerbate the secondary liver injury observed in many IBD patients. 60 Notably, several molecules, including monotropein, 61 beta-patchoulene, 62 and gingerenone A, 63 have demonstrated the ability to regulate different signaling pathways and alleviate secondary liver injury induced by colitis, highlighting their potential as treatment options.…”

Ferroptosis: a new mechanism of traditional Chinese medicine for treating ulcerative colitis

“…By assessing the activity of Fe 2+ , TNF-α, IL-1β, IL-6, GPX4 and Nrf2 , it’s found that Gingerenone A can downregulate Fe 2+ , TNF-α, IL-1β, and IL-6 while upregulating GPX4 expression. The mechanism is Gingerenone A can regulate iron metabolism pathways by activating the Nrf2 /GPX4 pathway, thereby controlling and alleviating ferroptosis in DSS-induced murine UC, ultimately mitigating UC ( Chen et al, 2022 ). High doses of Gingerenone A have a greater therapeutic effect on UC than 5-aminosalicylic acid.…”

“…Modern pharmacological studies have demonstrated that TCM can prevent and treat UC through various mechanisms, such as reducing oxidative stress, regulating autophagy, and exerting anti-inflammatory effects. Among these mechanisms, TCM targeting ferroptosis has shown significant efficacy ( Chen et al, 2022 ).…”