Ginsenoside Rc, as an FXR activator, alleviates acetaminophen-induced hepatotoxicity via relieving inflammation and oxidative stress

Abstract

Acetaminophen (APAP) intake leads to excessive NAPQI deposition, stimulating inflammatory and oxidative stress and causing fatal liver injury. However, the detailed molecular mechanism involved is unknown, and effective therapeutic approaches remain insufficient. In this study, we discovered that treatment with ginsenoside Rc can prevent the inflammatory response caused by APAP and oxidative stress in mouse primary hepatocytes (MPHs), along with the corresponding changes in related genes. Additionally, Ginsenoside Rc effectively alleviates APAP-induced cellular apoptosis and NAPQI accumulation in MPHs. In vivo, Ginsenoside Rc administration remarkably attenuates APAP-induced hepatotoxicity, repairing liver damage and improving survival. Moreover, Ginsenoside Rc treatment modulates genes involved in APAP metabolism, leading to a decrease in NAPQI and resulting in the alleviation of fatal oxidative stress and inflammatory response after APAP exposure, along with the expression of their related indicators. Furthermore, our RNA-seq and molecular docking analysis implies that FXR expression and FXR transcriptional activity are stimulated by Ginsenoside Rc treatment. Notably, due to the lack of FXR in mice and MPHs, ginsenoside Rc can no longer play its original protective role against hepatotoxicity and cell damage caused by APAP, and it is difficult to improve the corresponding survival rate and prevent hepatic apoptosis, NAPQI generation, fatal oxidative stress, and the inflammatory response induced by APAP and the expression of related genes. In summary, our results indicate that Ginsenoside Rc could act as an effective FXR activator and effectively regulate FXR-induced antioxidant stress and eliminate inflammation while also having an anti-apoptotic function.

Gut–Liver Axis as a Therapeutic Target for Drug-Induced Liver Injury

“…Liu et al found that kaempferol-7-O-rhamnoside could bind to FXR and upregulate FXR gene expression to increase cell viability, enhance liver function, and ameliorate oxidative stress in APAP-treated human L02 hepatocytes [121]. Zhong et al reported that ginsenoside Rc could alleviate APAP-induced hepatotoxicity, inflammation, oxidative stress, and apoptosis by upregulating FXR expression in mice and mouse primary hepatocytes [122].…”

Therapeutic Applications of Ginseng Natural Compounds for Health Management

“…GRc has been reported to enhance bone development in ovariectomy-induced osteoporotic mice and to stimulate osteogenic differentiation in vitro through the Wnt/β-catenin signaling pathway [64]. Additionally, an in vivo study demonstrated that GRc administration significantly attenuated acetaminophen-induced hepatotoxicity, repaired liver damage, and improved survival [65]. In addition, in a dose-dependent manner, GRc reduced the proliferation and viability of 3T3L1 preadipocytes, adipocyte numbers, and lipid accumulation in maturing 3T3L1 preadipocytes, indicating it inhibited lipogenesis [66].…”