Na+/K+-ATPase Modulates Purinergic P2X3 Receptor Function to Drive Bone Cancer Pain

  • Research (Wash D C). 2025 Oct 20:8:0932. doi: 10.34133/research.0932.
Songqiang Huang  1 ,  Bo Peng  2 ,  Wanting Dong  1 ,  Jiapeng He  2 ,  Hanbin Chen  3 ,  Jin-Song Bian  3
Affiliations
  • 1. Affiliated Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
  • 2. School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
  • 3. Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
PMID: 41122266 DOI: 10.34133/research.0932
Abstract

Bone Cancer pain (BCP) is one of the most common types of chronic pain in Cancer patients, with a prevalence of up to 75%. However, the pathological mechanism and therapeutic approaches are limited. Here, we demonstrated that Na+/K+-ATPase α1 (NKAα1) is a critical regulator of nociception through interaction with purinergic P2X3 Receptor (P2X3R) in the dorsal root ganglion (DRG). Conditional knockout of NKAα1 in transient receptor potential vanilloid 1-positive (TRPV1+) neurons led to an increase in P2X3R-dependent CA2+ influx and neuronal hyperexcitability and also promoted pain hypersensitivity in BCP model mice. In addition, NKAα1 knockout in TRPV1+ neurons further enhanced C-C motif chemokine ligand 5 release, thereby exacerbating spinal glial cell activation and pain hypersensitivity in BCP mice. DR5-12D, a monoclonal antibody to stabilize the expression of NKAα1, markedly inhibited the hyperexcitability of DRG nociceptors and ameliorated pain hypersensitivity in BCP mice. Overall, NKAα1 modulates P2X3R-dependent CA2+ influx and the excitability of DRG nociceptors, thereby providing valuable theoretical guidance for the treatment of BCP.

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