2. Academic Validation
  3. SIK2 mediated mitochondrial homeostasis in spinal cord injury: modulating oxidative stress and the AIM2 inflammasome via CRTC1/CREB signaling

SIK2 mediated mitochondrial homeostasis in spinal cord injury: modulating oxidative stress and the AIM2 inflammasome via CRTC1/CREB signaling

  • J Neuroinflammation. 2025 Dec 3;22(1):283. doi: 10.1186/s12974-025-03606-0.
Nongtao Fang # 1,  Yongli Wang # 1 2,  Yige Chen 1,  Yikang Wang 1,  Jiawei Xu 1,  Yangyi Xie 1,  Xiangji Xia 1,  Yaosen Wu 3,  Xiangyang Wang 4,  Yao Li 5
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 2 Department of Orthopaedics, Huzhou Basic and Clinical Translation of Orthopaedics Key Laboratory, Huzhou Central Hospital, Huzhou, Zhejiang, China.
  • 3 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. [email protected].
  • 4 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. [email protected].
  • 5 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. [email protected].
  • # Contributed equally.
PMID: 41339921 DOI: 10.1186/s12974-025-03606-0
Abstract

Mitochondrial oxidative stress and the absent in melanoma 2 (AIM2) inflammasome play crucial roles in the regulation of secondary injury in patients with spinal cord injury (SCI). AIM2 responds to oxidative stress-mediated DNA damage, and this response leads to neuroinflammation. Salt-inducible kinase 2 (SIK2) is an AMPK-related protein kinase that plays a role in modulating cell metabolism and homeostasis. SIK2 and AIM2 are key molecules involved in metabolic regulation and the innate immune response, respectively. There is a potential association between SIK2 and AIM2 in terms of the cellular stress response, DNA damage repair and inflammatory signal transduction. However, the detailed role and mechanisms remain to be fully elucidated in the context of SCI. The present study revealed that SIK2 and AIM2 increase the number of microglia after SCI. Moreover, pharmacological inhibition of SIK2 or genetic deletion of AIM2 improves functional recovery. In addition, the SIK2 Inhibitor ARN-3236, which alleviates the neuroinflammatory response, attenuates mitochondrial dysfunction and represses AIM2 activation in microglia. Mechanistically, SIK2 inhibition reduces Drp1-dependent mitochondrial fission through the CRTC1/CREB pathway, thereby decreasing mitochondrial DNA (mtDNA) leakage and AIM2 inflammasome activation, which inhibits the release of pyroptosis-related proteins and proinflammatory cytokines, ultimately mitigating neuroinflammation after SCI. Furthermore, SIK2-mediated neuroinflammation and functional recovery are related to AIM2. Thus, modulating microglial function through inhibition of SIK2 may be a viable therapeutic strategy for promoting functional recovery after SCI.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-025-03606-0.

Keywords

Absent in melanoma 2; Microglia; Mitochondria; Salt-inducible kinase 2; Spinal cord injury.

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