Targeting GPX2 to disrupt lipid homeostasis and enhance cisplatin sensitivity in diffuse gastric cancer

Diffuse gastric cancer (DGC) is characterized by high malignancy and metastasis rate, and poorly understood etiology, culminating in dismal patient outcomes. Here, through comprehensive analysis, we identified that glutathione peroxidase 2 (GPX2) plays a pivotal role in the progression of DGC by regulating lipid metabolism. This study demonstrates that GPX2 is markedly upregulated in DGC tissues, establishing its potential as an independent prognostic indicator. Functionally, GPX2 suppression disrupts lipid droplet formation and lipid homeostasis, leading to increased acylcarnitine levels that impair mitochondrial function. This disruption synergizes with endoplasmic reticulum stress to trigger apoptosis in gastric cancer cells. Notably, inhibiting GPX2 enhances the efficacy of cisplatin by sensitizing cancer cells to apoptosis. These insights identify GPX2 not only as a vital prognostic biomarker but also as a promising therapeutic target for overcoming cisplatin resistance in DGC, offering new avenues for treatment strategies.