NPR1 Promotes Lipid Droplet Lipolysis to Enhance Mitochondrial Oxidative Phosphorylation and Fuel Gastric Cancer Metastasis

Abstract Metabolic reprogramming driven by oncogenes plays a critical role in promoting and sustaining multiple steps of gastric cancer metastasis. However, the key metabolic driver of metastasis that can lead to the development of targeted therapies for preventing and treating metastatic gastric cancer remains elusive. Here, it is identified that the transmembrane guanylate cyclase, natriuretic peptide receptor 1 (NPR1), promoted gastric cancer lymph node metastasis by activating lipid droplet lipolysis and enhancing mitochondrial oxidative phosphorylation (OXPHOS). Clinical analysis reveals that elevated NPR1 protein level is correlated with increased lymph node metastasis and shorter patient survival. Functionally, NPR1 induced lipolysis of stored lipid droplets, releasing bioavailable fatty acids that are imported into mitochondria to upregulate OXPHOS, thus fueling the energy required for the metastasis of gastric cancer cells. Mechanistically, NPR1 activates protein kinase cGMP‐dependent 1 (PRKG1 or PKG), which directly bound to and activated hormone‐sensitive lipase (HSL) by phosphorylation at residues Ser ⁸⁵⁵ and Ser ⁹⁵¹ , thereby increasing lipolysis. Furthermore, targeted delivery of NPR1 siRNA using engineered exosome mimetics effectively suppressed gastric cancer metastasis. Taken together, these findings elucidate the NPR1‐driven metabolic mechanism underlying gastric cancer metastasis and suggest NPR1 as a promising therapeutic target for patients with metastatic gastric cancer.