Quercetin targets IL6/JAK1/STAT3/MMP9 signaling to attenuate breast cancer progression in diabetic comorbidity: A multi-omics and experimental study.

[BACKGROUND] Breast cancer and diabetes exhibit a bidirectional relationship, with diabetes elevating breast cancer risk/mortality and cancer therapies potentially increasing diabetic susceptibility. While the natural flavonoid quercetin shows dual anti-cancer/anti-diabetic efficacy, its mechanisms against this comorbidity remain unknown. This study aims to: (1) validate shared molecular targets linking both diseases; (2) identify quercetin's therapeutic targets; (3) elucidate its mechanisms via multi-omics and experimental validation.

[METHODS] We constructed a prognostic risk model using breast cancer-diabetes molecular targets from clinical databases. Quercetin's targets were screened via bioinformatics, followed by functional enrichment analysis. Molecular docking and molecular dynamics simulations quantified binding affinities between quercetin and core targets. Anti-metastatic efficacy and mechanisms were validated in vitro using breast cancer cell lines and in vivo mouse experiments.

[RESULTS] Key targets (IL6 and MMP9) significantly associated with breast cancer-diabetes prognosis were identified. Quercetin potently binds to core targets regulating JAK1/STAT3 signaling pathways, insulin resistance, and cell cycle. Mechanism experiments demonstrate that quercetin suppresses the activation of the IL6/JAK1/STAT3/MMP9 signaling pathway-induced by high glucose in vitro and in diabetic tumors in vivo-counteracting its promotion of proliferation, apoptosis resistance, and EMT/metastatic potential in breast cancer cells.

[CONCLUSION] Quercetin mitigates breast cancer-diabetes progression by targeting hub genes involved in IL6/JAK1/STAT3/MMP9 signaling pathway and metabolic dysregulation. This study provides a mechanistic foundation for quercetin as a precision therapeutic target in breast cancer with diabetes comorbidity.