Targeting Supramolecular Active Complexes of Nav1.7/Nav1.8 to Relieve Chronic Neuropathic Pain

  • Adv Sci (Weinh). 2026 May 20:e22185. doi: 10.1002/advs.202522185.
Liting Sun  1 ,  Hang Xian  2  3 ,  Yunxin Shi  1  2 ,  Taotan Yang  1  4 ,  Hongyan Shuai  5 ,  Wenchao Hu  2 ,  Siying Fei  1 ,  Miao Xu  1  6 ,  Taoyuan Yang  1 ,  Ruilong Xia  1 ,  Ting Wen  1 ,  Fengting Zhu  1  5 ,  Yan Fu  1 ,  Yang Li  1 ,  Wei Xia  1 ,  Ran Qian  1 ,  Yuanying Liu  2 ,  Zhicheng Tian  2 ,  Lamei Li  2 ,  Qian Zhou  1 ,  Lize Xiong  6 ,  Rui Cong  3 ,  Ceng Luo  2 ,  Shengxi Wu  2 ,  Xiafeng Shen  1 ,  Xin Yu  5 ,  Rou-Gang Xie  2  7 ,  Changgeng Peng  1  6
Affiliations
  • 1. The First Rehabilitation Hospital of Shanghai, Brain and Spinal Cord Innovation Research Center, Translational Research Institute of Brain and Brain-Like Intelligence，Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center For Anesthesiology and Perioperative Medicine, School of Medicine, Tongji University, Shanghai, China.
  • 2. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
  • 3. Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 4. Xiang-Xing College, Hunan University of Traditional Chinese Medicine, Changsha, China.
  • 5. Pre-clinical College, Dali University, Dali, Yunnan, China.
  • 6. Department of Anesthesiology and Perioperative medicine, Shanghai Fourth People's Hospital, Shanghai, China.
  • 7. The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi'an, China.
PMID: 42159924 DOI: 10.1002/advs.202522185
Abstract

Neuropathic pain (NP) affects 7%-10% of population, with current treatments often proving inadequate. Here we show that Nav1.7 and Nav1.8 form supramolecular active complexes (SMACs) with polygonal lattice structure in dorsal root ganglion (DRG) neurons of mouse models and patients with severe chronic NP. TrkB signaling facilitates the formation of Nav1.7/Nav1.8 SMACs. Targeting these SMACs with combined Nav1.7 and Nav1.8 blockers inhibits action potentials of both human and mouse pathological DRG neurons and synergistically alleviates chronic NP in spared nerve injury (SNI) and diabetic mouse models. The SMAC formation is promoted by five cytoskeletal proteins (SPTAN1, DSP, AHNAK, MPZ and PRX). Functional study demonstrates that these SMACs create a Na+ potential difference to amplify sodium currents, promoting DRG neuron hyperexcitability. Moreover, knockdown of these five cytoskeletal proteins prevents action potential generation in DRG neurons and eliminates NP in SNI mice. Our findings support that SMACs can be a potential pathological hallmark and novel promising therapeutic target for severe chronic NP.

Keywords
Creb; Dsp; Sptan1; TrkB; chronic pain; pathological hallmark; targeted therapy.
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