Breviscapine targets EGFR and SRC to abrogate diabetes-driven GPX4 lactylation and ferroptosis resistance in gastric cancer.

Mounting evidence identifies cancer as the leading cause of death in diabetic patients, necessitating therapies that disrupt this pathological nexus. We demonstrate that the flavonoid breviscapine inhibits diabetes-accelerated gastric cancer through a novel 'contextual programmed lethality' mechanism targeting the lactylation-ferroptosis axis. Employing network pharmacology, molecular dynamics simulations, and in vitro experiments, we revealed EGFR and SRC as core breviscapine targets within AGEs-RAGE-glycolytic networks, with molecular dynamics confirming stable high-affinity binding (ΔG < -4.39 kcal/mol; RMSF < 0.15 nm). Crucially, we identified a diabetes-specific vulnerability: AGEs-induced lactylation stabilizes GPX4 (half-life >24 h), conferring ferroptosis resistance. Breviscapine reverses this by: 1) dismantling lactylation-dependent GPX4 stabilization (half-life reduced to 5.1 ± 0.4 h), and 2) co-opting restored cholesterol synthesis (+2.3-fold) to fuel lethal lipid peroxidation (LPO increased 3.2-fold). This dual action selectively suppressed AGEs-driven malignancy-reducing proliferation by 63 ± 5.2 % and migration by 58 ± 4.3 %-while reversing Warburg metabolism (lactate decreased to 82 ± 7 % baseline). Efficacy was abrogated by LDHA overexpression or HMGCR inhibition, confirming mechanistic specificity. By exploiting metabolic rewiring to induce iron-dependent death exclusively in diabetic microenvironments, breviscapine emerges as a novel therapeutic strategy against diabetes-aggravated cancers.