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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\u2010dependent 1 (PRKG1 or PKG), which directly bound to and activated hormone\u2010sensitive lipase (HSL) by phosphorylation at residues Ser\n                    <jats:sup>855<\/jats:sup>\n                    and Ser\n                    <jats:sup>951<\/jats:sup>\n                    , 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\u2010driven metabolic mechanism underlying gastric cancer metastasis and suggest NPR1 as a promising therapeutic target for patients with metastatic gastric cancer.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503233","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T09:44:56Z","timestamp":1750412696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["NPR1 Promotes Lipid Droplet Lipolysis to Enhance Mitochondrial Oxidative Phosphorylation and Fuel Gastric Cancer Metastasis"],"prefix":"10.1002","volume":"12","author":[{"given":"Huafeng","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery Digestive Medicine Center The Seventh Affiliated Hospital Sun Yat\u2010sen University  Shenzhen 518107 P. R. 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