2. Academic Validation
  3. Betulinic acid enhances autopahgy to promote microglial M2 polarization and alleviate inflammation via AMPK-HDAC5-KLF2 signaling pathways in spinal cord injury

Betulinic acid enhances autopahgy to promote microglial M2 polarization and alleviate inflammation via AMPK-HDAC5-KLF2 signaling pathways in spinal cord injury

  • Int Immunopharmacol. 2025 Jun 17:158:114889. doi: 10.1016/j.intimp.2025.114889.
Zili He 1,  Yitie Xu 2,  Yu Zhang 2,  Mengqi Jin 2,  Yinuo Sun 3,  Fangying Tang 3,  Chuangqi Qiu 3,  Abass Mashud Akinfemi Junior 3,  Yunhao Cai 3,  Xiaodan Xu 3,  Xianghang Chen 2,  Kongbin Chen 4,  Guangheng Xiang 4,  Jian Xiao 5,  Jian Wang 6,  Jing Wang 7,  Baoyi Chen 8
Affiliations

Affiliations

  • 1 Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, China.
  • 2 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, China.
  • 3 Department of Wound Healing, Department of Spine Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 4 Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 5 Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, China; Department of Wound Healing, Department of Spine Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 6 Department of Wound Healing, Department of Spine Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China. Electronic address: jianwang0516@126.com.
  • 7 Department of Wound Healing, Department of Spine Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China. Electronic address: wjspine@163.com.
  • 8 Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, China. Electronic address: chenbaoyi@wmu.edu.cn.
PMID: 40388862 DOI: 10.1016/j.intimp.2025.114889
Abstract

Spinal cord injury (SCI) leads to neuroinflammation and activates microglia, which are crucial contributors to neurological deficits. Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, has demonstrated effectiveness in treating inflammatory and neurological disorders. This study aims to explore the potential role and underlying mechanism of BA in modulating microglial activation and inflammation in the context of SCI. Using a mouse SCI model, we assessed motor recovery via Basso Mouse Scale (BMS) and neuronal survival via H&E/Nissl staining. Western blotting, qPCR, immunofluorescence, and flow cytometry were employed to analyze microglial polarization, Autophagy, and AMPK-HDAC5-KLF2 signaling in vivo and in LPS-stimulated BV2 cells. Our findings reveal that BA significantly enhances functional recovery and reduces neuronal Apoptosis following SCI. Furthermore, BA facilitates the phenotypic transition of microglia from the M1 to M2 phenotype, thereby decreasing inflammatory factors in both the SCI model and LPS-stimulated BV2 cells. BA treatment restores the disrupted Autophagy flux in microglia induced by SCI or LPS, which in turn mitigates M1 polarization and inflammation. Mechanistically, BA restores Autophagy flux by activating the AMPK-HDAC5-KLF2 axis, thereby shifting microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype.

Keywords

Autophagy; Betulinic acid; Kruppel-like factor 2; Microglia; Neuroinflammation; Polarization; Spinal cord injury.

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