Triphala Targets the SLC7A11-GSH-GPX4 Axis to Trigger Ferroptosis in Oral Cancer: An Integrated Network Pharmacology,...

Triphala is a traditional three-fruit formulation with potential anticancer activity, but its ferroptosis-related mechanisms in oral cancer remain unclear. We integrated network pharmacology, transcriptomic analyses, prognostic modeling, Mendelian randomization, immune and drug-response analyses, molecular docking, and in vitro validation to investigate the Triphala-ferroptosis-oral cancer axis. Fifty-eight candidate functional genes were identified, and an eight-gene signature comprising AKR1C3, CA9, EGFR, GSTA1, MAPK8, MGST1, PPARG, and RB1 showed prognostic value across multiple cohorts. Mendelian randomization supported causal associations of MAPK8, MGST1, and PPARG with oral cancer risk. Seven Triphala-derived compounds, including epigallocatechin gallate, quercetin, kaempferol, luteolin, ellagic acid, gallic acid, and quinine, displayed favorable predicted interactions with key targets. In CAL-27 cells, Triphala altered the expression of signature genes, reduced GPX4 and SLC7A11 protein levels, increased Fe²⁺and malondialdehyde, depleted glutathione and glutathione peroxidase activity, and enhanced lipid peroxidation; these effects were partially modulated by ferrostatin-1. This study advances the field by linking Triphala to a ferroptosis-based prognostic framework and experimentally demonstrating its regulation of the SLC7A11-GSH-GPX4 axis in oral cancer.