Oroxin A Induces Autophagic Cell Death in Gastric Cancer Cells Through the MAPK/ERK/REDD1 Axis

ABSTRACT Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide, with limited treatment efficacy and high drug resistance. Natural compounds offer promising therapeutic potential due to their multitarget and low‐toxicity profiles. This study aimed to explore the anticancer effects of Oroxin A (OA), a natural flavonoid, and its underlying mechanisms in gastric cancer. A series of in vitro assays and organoid models were used to assess OA's effects on cell viability, proliferation, and migration. Mechanistic investigations included RNA‐sequencing, Western blot analysis, immunofluorescence, and electron microscopy. OA significantly inhibited gastric cancer cell growth and migration while showing minimal toxicity to normal gastric epithelial cells. OA induced autophagic, rather than apoptotic, cell death. Mechanistically, OA activated the MAPK/ERK signaling pathway, upregulated REDD1, and inhibited mTOR signaling, leading to enhanced autophagy. REDD1 overexpression amplified this effect, whereas knockdown reversed it. OA induces autophagic cell death in gastric cancer cells via the MAPK/ERK/REDD1 pathway, providing a promising natural compound candidate for gastric cancer therapy.