Fang-Yi Long

Background: 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‐HT₇R) could serve as a potential pattern recognition receptor (PRR) for ADP‐hep, yet the precise mechanism of ADP‐hep's regulation on 5‐HT₇R remains unclear.Aims: 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‐HT₇R signaling in mediating neuroinflammation and cognitive impairment in mice.Results: We found that 5‐HT₇R may act as a potential PRR for ADP‐hep and potentially bind to ADP‐hep. 5‐HT₇R 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‐HT₇R 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.Conclusion: In summary, 5‐HT₇R 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.

The FGF receptors (FGFRs) belong to a family of receptor tyrosine kinases. Abundant evidence shows that FGFRs are closely related to tumor cell invasion and angiogenesis. Hence, targeted modulation... Graphical abstract

Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure–activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.