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

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

  • Adv Sci (Weinh). 2025 Jun 20:e03233. doi: 10.1002/advs.202503233.
Huafeng Fu 1 2,  Jie Zhang 1,  Hengxing Chen 3,  Haobin Hou 1,  Huanjie Chen 2 4,  Rongman Xie 1,  Yanlei Chen 4 5,  Jian Zhang 1,  Dehua Liu 1,  Leping Yan 3 5,  Rui L Reis 6 7,  Joaquim M Oliveira 6 7,  Yulong He 1 3 8,  Li Zhong 3 5,  Qinbo Cai 2 4,  Dongjie Yang 1 3 8
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Digestive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, P. R. China.
  • 2 General Surgery Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, P. R. China.
  • 3 Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, P. R. China.
  • 4 Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China.
  • 5 Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, P. R. China.
  • 6 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Zona Industrial da Gandra, Barco, 4805-017, Guimarães, Portugal.
  • 7 ICVS/3B's - PT Government Associate Laboratory, Braga, 4805-017, Guimarães, Portugal.
  • 8 Research Center for Diagnosis and Treatment of Gastric Cancer, Sun Yat-sen University, Guangzhou, P. R. China.
PMID: 40539884 DOI: 10.1002/advs.202503233
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 Ser855 and Ser951, 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.

Keywords

engineered cell membrane‐derived exosome mimetics; gastric cancer; lipid droplet; lipolysis; lymph node metastasis; mitochondrial oxidative phosphorylation; natriuretic peptide receptor 1.

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