2. Academic Validation
  3. Sophoridine alleviates sepsis-associated encephalopathy by inhibiting MARK4 and NLRP3 signaling

Sophoridine alleviates sepsis-associated encephalopathy by inhibiting MARK4 and NLRP3 signaling

  • Free Radic Biol Med. 2025 Oct 28:S0891-5849(25)01324-3. doi: 10.1016/j.freeradbiomed.2025.10.293.
Kunmei Xie 1,  Jingquan Dong 2,  Xiguang Liu 3,  Xiao Liu 2,  Shasha Zhang 2,  Yan Cao 2,  Long Chen 2,  Wanyi Xu 2,  Panpan Zhao 4,  Zibo Dong 5
Affiliations

Affiliations

  • 1 Institute of Neuroscience, Department of Neurosurgery, The Afffliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China; Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
  • 2 Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
  • 3 Institute of Neuroscience, Department of Neurosurgery, The Afffliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China.
  • 4 Institute of Neuroscience, Department of Neurosurgery, The Afffliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang 222000, China. Electronic address: zhaopanpan@njmu.edu.cn.
  • 5 Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China. Electronic address: 2018000011@jou.edu.cn.
PMID: 41167535 DOI: 10.1016/j.freeradbiomed.2025.10.293
Abstract

Sepsis is a life-threatening systemic inflammatory response syndrome with high morbidity and mortality. A frequent complication is sepsis-associated encephalopathy (SAE), characterized by neurological impairments. Microglia pyrin domain- containing receptor 3 (NLRP3) inflammasome activation is a pivotal pathogenic mechanism in SAE. Microtubule-affinity regulating kinase 4 (MARK4) has been implicated in neuroinflammatory diseases, but its role in SAE and microglial NLRP3 inflammasome activation is unclear. Sophoridine (SRI), a MARK4 antagonist with anti-inflammatory and neuroprotective properties, has not yet been thoroughly investigated in SAE. Here, we used a cecum ligation puncture (CLP)-induced SAE mouse model and LPS+ATP or LPS+ nigericin (Nig)-treated microglia, to assess the role of MARK4 in SAE. Molecular docking, Nissl staining, the enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and behavioral tests were applied to assess SRI's effects on SAE. Our findings demonstrate that MARK4 is significantly upregulated in SAE. Knockdown of MARK4 effectively suppressed microglial Pyroptosis and pro-inflammatory cytokine release by inhibiting NLRP3 inflammasome activation. SRI binds to MARK4 and enhances its stability. By suppressing MARK4 protein expression, SRI reduces NLRP3 inflammasome-mediated microglia inflammation. In vivo, SRI treatment increased survival, improved neurological behavioral deficits, attenuated blood-brain barrier disruption, and provided neuroprotective effects against brain injury. In summary, MARK4 contributes to microglial Pyroptosis and neuroinflammation through NLRP3 pathway in SAE, resulting in neuronal injury and cognitive impairment. SRI alleviates SAE by targeting MARK4. These results suggest MARK4 as a potential therapeutic target and SRI as a promising candidate for treating SAE.

Keywords

MARK4; NLRP3 inflammasome; Neuroinflammation; Sepsis-associated encephalopathy; Sophoridine.

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