Ginsenoside Rd Inhibited Ferroptosis to Alleviate CCl₄-Induced Acute Liver Injury in Mice via cGAS/STING Pathway

Abstract

Carbon tetrachloride (CCl4)-induced lipid peroxidation associated with hepatic oxidative stress and cell death is an important mechanism of acute liver injury (ALI). Ginsenoside Rd is considered an active ingredient of ginseng. Evidence suggests that ginsenoside Rd may improve ischaemic stroke, nerve damage, cancer and other diseases involving apoptosis, inflammation, oxidative stress, mitochondrial injury and autophagy. However, the effects of ginsenoside Rd on CCl4-induced ALI and its underlying mechanisms are still unclear. In this study, 0.25% CCl4 was injected intraperitoneally in mice to establish a CCl4-induced ALI model. In the Rd treatment group, Rd (10, 20[Formula: see text]mg/kg) doses were injected intraperitoneally 1[Formula: see text]h before and 23[Formula: see text]h after CCl4 administration. Ferroptosis inducer imidazole ketone erastin (IKE) was injected intraperitoneally 4[Formula: see text]h before CCl4 administration to explore the mechanism. The blood and liver were collected 24[Formula: see text]h after CCl4 administration to investigate the effect and mechanism of ginsenoside Rd on CCl4-induced ALI. Our results showed that ginsenoside Rd inhibited CCl4-induced ALI in mice. Ginsenoside Rd also downregulated CCl4-induced serum and liver iron, 4-hydroxynonenal, and 8-hydroxy-2 deoxyguanosine levels. Furthermore, it upregulated glutathione and glutathione peroxidase 4 levels. In addition, ginsenoside Rd downregulated the expression of cGAS and STING. Subsequently, the ferroptosis inducer imidazole ketone erastin significantly reversed the hepatoprotective effect and influence of ginsenoside Rd with regard to the indicators mentioned above. Our study confirmed that ginsenoside Rd ameliorated CCl4-induced ALI in mice, which was related to the reduction of ferroptosis. Simultaneously, the ginsenoside Rd-mediated inhibition of the cGAS/STING pathway contributed to its antiferroptosis effect. In conclusion, our results suggested that ginsenoside Rd inhibited ferroptosis via the cGAS/STING pathway, thereby protecting mice from CCl4-induced ALI. These results suggested ginsenoside Rd may be used as a potential intervention treatment against CCl4-induced ALI.

Activation of STING signaling aggravates chronic alcohol exposure‐induced cognitive impairment by increasing neuroinflammation and mitochondrial apoptosis

“…12 In cases of In addition to its established role in facilitating the innate immune response, alternative functions of STING signaling, including its involvement in apoptosis, ferroptosis, and autophagy, have been reported. [6][7][8] Prolonged activation of STING triggers mitochondriadependent apoptosis in B cells. 52 A STING agonist, diABZI, induces the cleavage of caspase 3 and contributes to the development of acute respiratory distress syndrome (ARDS).…”

“…5 Apart from inflammatory responses, emerging studies suggest that activation of the STING is involved in various forms of cellular death processes, such as autophagy, ferroptosis, apoptosis, pyroptosis, and necroptosis. [6][7][8] Activation of the STING signaling pathway has been implicated in pathological changes associated with autoimmune diseases, infections, and CNS diseases. [9][10][11][12] Alcohol (ethanol, EtOH) is one of the most commonly consumed addictive substances worldwide and alcohol use disorder (AUD) is increasingly emerging as a significant global issue of concern.…”

TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling

“… 57 The inhibition of ferroptosis ameliorated acute liver damage by inhibiting STING activation. 65 However, STING signalling plays a crucial role in numerous forms of cell death, including ferroptosis. 66 , 67 Moreover, co-immunoprecipitation studies demonstrated that STING could interact with the TAK1 protein, indicating an interaction between STING and TAK1.…”

cGAS‐STING signaling in cell death: Mechanisms of action and implications in pathologies

“…During acute kidney injury, elevated phosphoglycerate mutase 5 can dephosphorylate Bax, thereby promoting mtDNA leakage to trigger cGAS‐STING activation, progress critical in kidney pathogenesis [133]. Ginsenoside Rd, an active ingredient of ginseng, attenuates ferroptosis via inhibiting cGAS‐STING signaling from ameliorating CCl 4 ‐induced acute liver injury [137]. These various studies collectively suggest a central role of cGAS‐STING signaling in acute organ injuries via its intricate interaction with distinct types of cell death.…”