R-type ginsenoside Rg3 attenuates cisplatin-induce intestinal injury via restoring autophagy flux blockade

Cisplatin and its metabolites can cause severe gastrointestinal mucosal damage, leading to varying degrees of intestinal injury in nearly all patients following administration. Although the anti-tumor effectiveness of R-ginsenoside Rg3 (R-Rg3, a key chemical component of Shen Yi Capsule) as the first-line drug is widely recognized in the clinic, there is less concern about the improved effects of R-Rg3 against intestinal toxicity caused by concurrent cisplatin chemotherapy. This study aimed to investigate the protective effects of R-Rg3 against cisplatin-induced intestinal toxicity and to explore its potential molecular targets and mechanisms. Rats in the R-Rg3 treatment group were treated with R-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 R-Rg3 treatment group on the 7^th day. Intestinal epithelial cell line 6 (IEC-6) were pretreated with R-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, R-Rg3 treatment for 7 days markedly alleviated cisplatin-induced oxidative stress and mitochondrial dysfunction in vivo, while suppressing excessive autophagy and reducing intestinal damage. In IEC-6 cells, R-Rg3 pretreatment inhibited mitophagy 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 R-Rg3 action. Importantly, application of 3-methyladenine and Bafilomycin A1 verified that R-Rg3 could alleviate gastrointestinal dysfunction by restoring the cisplatin-induced autophagic flux blockade. In conclusion, this study identifies a previously underappreciated protective role of R-Rg3 against cisplatin-induced intestinal injury. Furthermore, it suggests that pharmacological modulation of the mitochondria–lysosome axis by R-Rg3 may effectively mitigate oxidative stress–mediated autophagic flux impairment caused by cisplatin.