2. Academic Validation
  3. Urolithin A alleviates NLRP3 inflammasome activation and pyroptosis by promoting microglial mitophagy following spinal cord injury

Urolithin A alleviates NLRP3 inflammasome activation and pyroptosis by promoting microglial mitophagy following spinal cord injury

  • Int Immunopharmacol. 2025 Feb 20:148:114057. doi: 10.1016/j.intimp.2025.114057.
Kongbin Chen 1,  Jiahao Ying 1,  Jiangwei Zhu 2,  Liang Chen 1,  Rongjie Liu 1,  Mengqi Jing 2,  Yuchao Wang 3,  Kailiang Zhou 1,  Long Wu 4,  Chenyu Wu 5,  Jian Xiao 6,  Wenfei Ni 7
Affiliations

Affiliations

  • 1 Department of Orthopedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000 China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000 China.
  • 2 Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000 China.
  • 3 Department of Orthopedic, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116600, China.
  • 4 Department of Orthopedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000 China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000 China. Electronic address: wmuwulong@163.com.
  • 5 Department of Orthopedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000 China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000 China; Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000 China. Electronic address: wuchenyu0613@126.com.
  • 6 Department of Orthopedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000 China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000 China; Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000 China. Electronic address: xfxj2000@126.com.
  • 7 Department of Orthopedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000 China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou 325000 China; Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000 China. Electronic address: niwenfei@126.com.
PMID: 39827665 DOI: 10.1016/j.intimp.2025.114057
Abstract

Spinal cord injury (SCI) is a potentially fatal condition that often results in loss of motor and sensory functions, thereby significantly burdening global health initiatives. Urolithin A (UA), an intestinal microbial metabolite of ellagic acid, is known for its potent anti-inflammatory properties in chronic inflammation contexts. UA treatment in humans induces a molecular signature of improved mitochondrial and cellular health. Yet, its effects on acute inflammation following SCI remain unclear. In this study, we developed an impact-induced mouse model for SCI and treated the injured mice with UA (50 mg/kg/d, till 8 weeks) via intragastric administration. Furthermore, we subjected BV2 cells to lipopolysaccharide and adenosine 5'-triphosphate to simulate the post-injury inflammatory response. Our results demonstrated that pre-treatment with UA (10 μM) effectively inhibited NLRP3 inflammasome activation in LPS-primed BV2 cells. This inhibition was evidenced by reduced cleaved Caspase-1 and mature IL-1β release, diminished ASC speck formation, and decreased gasdermin D (GSDMD)-mediated Pyroptosis. Additionally, UA treatment restored mitochondrial activity and ROS production attenuated by NLRP3 activation, increased LC3-II expression, and enhanced LC3 co-localization with mitochondria. 3-Methyladenine (3-MA), an Autophagy Inhibitor, can partially reverse the stimulatory effect of UA on Mitophagy, as well as the inhibitory effect of UA on Pyroptosis. This study highlighted the protective role of UA against SCI through its promotion of Mitophagy, which in turn inhibits NLRP3 inflammasome activation and Pyroptosis.

Keywords

Autophagy; Mitophagy; NLRP3 inflammasome; Pyroptosis; Spinal cord injury; Urolithin A.

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