Mitochondrial Dysfunction as a Targetable Vulnerability in Gastric Cancer: From Carcinogenesis to Apoptosis (A Narrative Review).

Gastric cancer (GC) remains a major global health burden and is associated with high mortality worldwide. Current treatment integrates surgery, perioperative or systemic chemotherapy, molecularly targeted therapy, and immune checkpoint blockade; however, efficacy is frequently limited by intratumoral heterogeneity, metabolic plasticity, and therapeutic resistance. Mitochondria, as central regulators of cellular bioenergetics, redox homeostasis, and apoptotic signaling, are profoundly altered in GC. Tumor cells frequently exhibit enhanced aerobic glycolysis accompanied by suppressed oxidative phosphorylation, reflecting mitochondrial metabolic remodeling. Accumulating evidence indicates that mitochondrial dysfunction actively contributes to tumor initiation, progression, and therapeutic resistance in GC. Importantly, these mitochondrial alterations also create metabolic vulnerabilities that may be therapeutically exploitable. Both conventional chemotherapeutic agents and herbal-derived natural compounds have been reported to induce mitochondrial stress responses, including excessive reactive oxygen species (ROS) accumulation, mitochondrial membrane potential loss, and activation of mitochondria-dependent intrinsic apoptotic pathways. In this narrative review, we summarize the major molecular mechanisms underlying mitochondrial dysfunction in GC, highlight mitochondrial-associated prognostic biomarkers, and discuss emerging therapeutic strategies targeting mitochondrial pathways. Collectively, these insights emphasize mitochondrial dysfunction as a candidate therapeutic vulnerability and support further investigation of mitochondria-centered therapeutic strategies for GC.