Ginsenoside Rg3 attenuates cisplatin-induce intestinal injury via restoring autophagy flux blockade

Cisplatin and its metabolites can inflict severe damage to the gastrointestinal mucosa, leading to varying degrees of gastrointestinal injury in nearly all patients’ post-administration. Although the anti-tumor effectiveness of ginsenoside Rg3 (Shen Yi Capsule) as the first-line drug is widely recognized in the clinic, there is less concern about the improved effects of Rg3 against intestinal toxicity caused by concurrent cisplatin chemotherapy. This study aims to investigate the protective effects of Rg3 against cisplatin-induced intestinal toxicity and to explore its potential molecular targets and mechanisms. Rg3 treatment group was treated with Rg3 (7, 14 mg·kg⁻¹, p.o.) for 7 days, and a single dose of cisplatin (14 mg·kg⁻¹, i.p.) was administered via intraperitoneal injection to rats in the cisplatin group and Rg3 treatment group on the 7th day. Intestinal epithelial cell line 6 (IEC-6) were pretreated with Rg3 (1.25, 2.5, 5 μmol·L⁻¹) for 24 h followed by cisplatin treatment (3 μmol·L⁻¹, 24 h). The in vivo results showed that, Rg3 treatment for 7 days could significantly reverse the oxidative stress and mitochondrial dysfunction caused by cisplatin, inhibited autophagy, thereby reduce intestinal damage. Pretreatment of IEC-6 cells with Rg3 for 24 h inhibited mitochondrial autophagy and promoted the restoration of lysosomal function. Autophagy inhibitors 3-Methyladenine (autophagosome formation inhibitor, 1 μmol·L⁻¹) and Bafilomycin A1 (proton pump inhibitor, 8 μmol·L⁻¹) were used to verify the mechanism of Rg3 action. Importantly, application of 3-Methyladenine and Bafilomycin A1 verified that Rg3 could alleviate gastrointestinal dysfunction by restoring the cisplatin-induced autophagic flux blockade. This study not only reveals a previously unrecognized protective role of ginsenoside Rg3 against cisplatin-induced intestinal injury, but also indicates that pharmacologically modulating mitochondria-lysosomes with Rg3 may effectively alleviate oxidative stress-mediated autophagic flux blockade caused by cisplatin.