Berberine exploits autophagy to combat gastric cancer: molecular mechanisms, therapeutic synergy, and translational perspectives

Gastric cancer (GC) remains a major global health challenge, driven in part by dysregulated autophagy that promotes tumor survival, progression, and resistance to therapy. Berberine (BBR), a bioactive isoquinoline alkaloid long recognized for its antimicrobial and anti-inflammatory properties, has recently garnered significant attention as a potent anti-cancer agent. This review highlights how BBR strategically exploits autophagy to suppress gastric tumorigenesis by modulating key molecular pathways, including PI3K/AKT/mTOR, AMPK, MAPK, and p53. Through this regulation, BBR disrupts critical cellular processes such as proliferation, metastasis, and resistance to cell-death programs. Moreover, its ability to orchestrate crosstalk between autophagy, apoptosis, and ferroptosis reveals powerful therapeutic synergy, positioning BBR as an attractive candidate for combinational treatments. Finally, we discuss emerging translational perspectives, emphasizing BBR’s potential to overcome chemoresistance and enhance treatment efficacy in clinical settings. Collectively, this review underscores berberine as a promising autophagy-targeting agent that may help reshape future therapeutic strategies for GC.