6-Shogaol attenuates cisplatin-induced gastrointestinal inflammation involving modulation of the putative mTOR/TFEB-mediated autophagy-lysosomal pathway.

Gastrointestinal (GI) inflammation is a predominant toxic side effect of cisplatin therapy in oncology patients. 6-Shogaol, among the most effective components derived from ginger, is effective in reducing inflammation, but its inhibitory effects on cisplatin-induced GI inflammation are unknown. This study investigates whether 6-shogaol control of cisplatin-induced GI inflammation is associated with the mTOR/TFEB-mediated autophagy-lysosomal pathway. GI inflammation was assessed by H&E staining and ELISA, while network pharmacology and molecular docking were employed to identify potential targets and mechanisms. Furthermore, the autophagy marker LC3 was detected by immunofluorescence, and the mTOR/TFEB pathway was evaluated by Western blot. 6-Shogaol treatment exerted therapeutic efficacy on GI inflammation via improving cisplatin-triggered reduction in body weight and ameliorated inflammatory pathological injury in mice, with decreased levels of IL-1β, IL-6, and TNF-α. Mechanistically, 6-shogaol increased LC3II/Ⅰ, CTSB, and LAMP1 protein expression; decreased p62 protein expression; and improved the autophagy-lysosomal pathway. Immunofluorescence confirmed increased LC3 expression, particularly at the high dose. Network pharmacology and molecular docking suggested that mTOR is a key putative target of 6-shogaol in the prevention and treatment of GI inflammation, and 6-shogaol treatment was associated with suppressed mTOR/TFEB phosphorylation and enhanced TFEB entry into the nucleus. These findings indicate that cisplatin-induced autophagy suppression and GI inflammation correlate with dysregulated mTOR/TFEB signaling, while 6-shogaol treatment was associated with attenuated GI injury in conjunction with modulation of the putative mTOR/TFEB-mediated autophagy-lysosomal pathway.