Solasonine inhibits growth of gastric cancer by targeting FTL-mediated ferroptosis.

Solasonine (SS), a principal bioactive constituent of Solanum nigrum L., has attracted considerable attention due to its pronounced cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of SS against gastric cancer remains inadequately explored. In this study, the therapeutic effects and potential targets of SS against gastric cancer were investigated. The results showed that SS markedly inhibited cell proliferation and promoted cell death in gastric cancer cells. Pharmacological inhibition studies revealed that the antitumor effects of SS predominantly rely on ferroptosis rather than apoptosis, necroptosis, or autophagy. This was corroborated by dysregulation of ferroptosis-related molecular markers, increased intracellular lipid peroxidation (LPO), malondialdehyde (MDA), and Fe2+ levels, and depletion of glutathione (GSH). Proteomic profiling identified ferritin light chain (FTL) as a putative target of SS, which was further supported by molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and western blot. Bioinformatics analyses demonstrated that FTL expression is significantly elevated at both the mRNA and protein levels in gastric cancer tissues. Higher FTL expression correlates with poorer overall survival. Overexpression of FTL in gastric cancer cells promoted the proliferation and mitigated SS-induced ferroptosis. In mice, SS treatment significantly inhibited tumor growth, suppressed FTL protein expression, and induced ferroptosis in gastric cancer xenografts. And the above effects can be rescued by application of a ferroptosis inhibitor. The antitumor activity and ferroptosis induction by SS were further validated using human organoid models. These findings demonstrate that SS inhibits gastric cancer growth by direct binding to FTL and promoting FTL-mediated ferroptosis. This mechanistic insight underscores the clinical applicability of SS for gastric cancer treatment.