Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (11): 3287-3301.doi: 10.4103/NRR.NRR-D-23-01256

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Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury

Ziwei Fan1, 2, #, Mengxian Jia1, 2, #, Jian Zhou1, 2, Zhoule Zhu1, 2, Yumin Wu1, 2, Xiaowu Lin1, 2, Yiming Qian2 , Jiashu Lian1, 2, Xin Hua2, 3, Jianhong Dong2 , Zheyu Fang2, 3, Yuqing Liu2 , Sibing Chen2 , Xiumin Xue2 , Juanqing Yue4 , Minyu Zhu1 , Ying Wang5, *, Zhihui Huang1, 2, *, Honglin Teng1, *   

  1. 1 Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China;  2 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China;  3 Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China;  4 Department of Pathology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China;  5 Department of Clinical Research Center, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China
  • Online:2025-11-15 Published:2025-02-25
  • Contact: Ying Wang, PhD, nancywangying@163.com; Zhihui Huang, PhD, huang0069@hznu.edu.cn; Honglin Teng, MD, tenghonglin@wzhospital.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82071387 (to HT), 81971172 (to YW); the Natural Science Foundation of Zhejiang Province, China, No. LY22H090012 (to HT); and the Basic Research Project of Wenzhou City, China, No. Y20220923 (to MZ).

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Abstract: The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury. Regulation of shifting microglia polarization from M1 (neurotoxic and proinflammatory type) to M2 (neuroprotective and anti-inflammatory type) after spinal cord injury appears to be crucial. Tryptanthrin possesses an anti-inflammatory biological function. However, its roles and the underlying molecular mechanisms in spinal cord injury remain unknown. In this study, we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro. Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway. Additionally, we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury, inhibited neuronal loss, and promoted tissue repair and functional recovery in a mouse model of spinal cord injury. Finally, using a conditional co-culture system, we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress–related neuronal apoptosis. Taken together, these results suggest that by targeting the cGAS/STING/NF-κB axis, tryptanthrin attenuates microglia–derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Key words: cGAS/STING, functional recovery, microglia, neuroinflammation, neuroprotection, nuclear factor-κB, polarization, spinal cord injury, tryptanthrin