Scholarlink

<p>Sepsis-associated encephalopathy (SAE) is a significant clinical condition leading to cognitive impairment, yet its molecular mechanisms remain to be fully elucidated. This study demonstrates that KANK4 expression is significantly downregulated in the hippocampus of SAE mice and in LPS-induced microglial cells, and this downregulation closely correlates with microglial overactivation and increased release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). Importantly, hippocampal overexpression of KANK4 not only markedly improved cognitive performance in SAE mice in the novel object recognition and Morris water maze (MWM) tests but also effectively alleviated hippocampal neuronal damage. Mechanistically, we confirmed that KANK4 directly binds to the 3’UTR of TMEM260 mRNA to enhance its stability, thereby inhibiting the O-mannosylation modification (with S117 as the key site) and protein expression of CXCL16. A series of functional experiments showed that TMEM260 overexpression significantly reduced CXCL16 levels and attenuated neuroinflammation, whereas CXCL16 overexpression completely reversed the neuroprotective effects of TMEM260. These findings reveal for the first time the crucial role of the KANK4-TMEM260-CXCL16 axis in regulating microglial activation, providing a new therapeutic target for SAE.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

KANK4 Regulates CXCL16 Glycosylation Through TMEM260 to Modulate Microglial Activation in Sepsis-associated Encephalopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月28日

查看全文
  • Mao Peng,
  • Sinian Tan,
  • Ao Li,
  • Qiong Guo,
  • Lin Liu

摘要

Sepsis-associated encephalopathy (SAE) is a significant clinical condition leading to cognitive impairment, yet its molecular mechanisms remain to be fully elucidated. This study demonstrates that KANK4 expression is significantly downregulated in the hippocampus of SAE mice and in LPS-induced microglial cells, and this downregulation closely correlates with microglial overactivation and increased release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). Importantly, hippocampal overexpression of KANK4 not only markedly improved cognitive performance in SAE mice in the novel object recognition and Morris water maze (MWM) tests but also effectively alleviated hippocampal neuronal damage. Mechanistically, we confirmed that KANK4 directly binds to the 3’UTR of TMEM260 mRNA to enhance its stability, thereby inhibiting the O-mannosylation modification (with S117 as the key site) and protein expression of CXCL16. A series of functional experiments showed that TMEM260 overexpression significantly reduced CXCL16 levels and attenuated neuroinflammation, whereas CXCL16 overexpression completely reversed the neuroprotective effects of TMEM260. These findings reveal for the first time the crucial role of the KANK4-TMEM260-CXCL16 axis in regulating microglial activation, providing a new therapeutic target for SAE.