Zou Xiao, Yang Yu-Xin, Yue Bing-Jie, Yang Han-Yinan, Yang Yan-Rong, Li Meng-Yang, Du Ou, Qiao Gan, Wu Yi-Jin, Du Jun-Rong, Long Fang-Yi
Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
CNS Neurosci Ther. 2025 Jun;31(6):e70455. doi: 10.1111/cns.70455.
ADP-heptose (ADP-hep), a soluble intermediate in the biosynthesis of lipopolysaccharide in Gram-negative bacteria, is known to trigger inflammation. Our research suggests that 5-hydroxytryptamine receptor 7 (5-HTR) could serve as a potential pattern recognition receptor (PRR) for ADP-hep, yet the precise mechanism of ADP-hep's regulation on 5-HTR remains unclear.
Based on the results of mRNA sequencing analysis, this study took ferroptosis of neurons and microglia as a starting point to explore the role and underlying mechanisms of ADP-hep/5-HTR signaling in mediating neuroinflammation and cognitive impairment in mice.
We found that 5-HTR may act as a potential PRR for ADP-hep and potentially bind to ADP-hep. 5-HTR deficiency significantly ameliorated cognitive dysfunction induced by ADP-hep in mice, as well as ferroptosis mediated by the p53/cystine-glutamate antiporter (xCT)/glutathione peroxidase 4 (GPX4) signaling pathway and its associated key markers. Furthermore, 5-HTR deficiency inhibited ferroptosis in neurons and M2-type microglia, mitigated the decline in the proportion of M2-type microglia, and subsequently suppressed the inflammatory microenvironment to promote neuronal survival, thereby exerting neuroprotective effects.
In summary, 5-HTR deficiency promotes cognitive recovery by alleviating the neuronal and microglial ferroptosis triggered by ADP-hep, subsequently dampening the inflammatory microenvironment to support neuronal viability. These findings provide a novel perspective and approach for the development of innovative therapeutic strategies for the treatment of cognitive impairment-related diseases.
ADP-庚糖（ADP-hep）是革兰氏阴性菌脂多糖生物合成中的一种可溶性中间体，已知可引发炎症。我们的研究表明，5-羟色胺受体7（5-HTR）可能作为ADP-庚糖的潜在模式识别受体（PRR），但ADP-庚糖对5-HTR的精确调控机制仍不清楚。
基于mRNA测序分析结果，本研究以神经元和小胶质细胞的铁死亡为切入点，探讨ADP-庚糖/5-HTR信号在介导小鼠神经炎症和认知障碍中的作用及潜在机制。
我们发现5-HTR可能作为ADP-庚糖的潜在PRR，并可能与ADP-庚糖结合。5-HTR缺陷显著改善了ADP-庚糖诱导的小鼠认知功能障碍，以及由p53/胱氨酸-谷氨酸反向转运体（xCT）/谷胱甘肽过氧化物酶4（GPX4）信号通路介导的铁死亡及其相关关键标志物。此外，5-HTR缺陷抑制了神经元和M2型小胶质细胞的铁死亡，减轻了M2型小胶质细胞比例的下降，随后抑制了炎症微环境以促进神经元存活，从而发挥神经保护作用。
综上所述，5-HTR缺陷通过减轻ADP-庚糖引发的神经元和小胶质细胞铁死亡来促进认知恢复，随后抑制炎症微环境以支持神经元活力。这些发现为开发治疗认知障碍相关疾病的创新治疗策略提供了新的视角和方法。
