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Here, we found that two weeks of SD induced marked hypothalamic neuroinflammation, accompanied by increased expression of the pro-inflammatory cytokines IL-1\u03b2, IL-6, and TNF-\u03b1, as well as the chemokine Ccl2, together with reduced neuronal markers, including decreased Nissl-body and NeuN+ cells. Single-nucleus RNA sequencing (snRNA-seq) suggested that inhibitory neurons exhibited prominent transcriptional responses to SD, including enrichment of inflammatory pathways such as TNF and IL-17 signaling and transcriptional programs associated with neuronal dysfunction. Furthermore, SD was also associated with microglial activation and a phenotypic shift toward a disease-associated state, exhibiting enhanced antigen-presenting and pro-inflammatory capacity. Notably, intercellular communication analysis identified the neural cell adhesion molecule 1 (NCAM1)\/fibroblast growth factor receptor 1 (FGFR1) signaling axis as a key mediator of crosstalk between microglia and other cell types. In BV2 cells, recombinant NCAM1 attenuated lipopolysaccharide-induced inflammatory responses in an Fgfr1-dependent manner. Consistently, PVN-targeted Fgfr1 knockdown in vivo exacerbated SD-associated microglial activation, neuroinflammation, and neuronal injury. Collectively, our findings elucidate a critical protective role for the NCAM1\/FGFR1 axis in mitigating SD-induced hypothalamic neuroinflammation and neuronal injury. This highlights this pathway as a candidate mechanism for further therapeutic investigation in sleep-related neurological dysfunction.<\/jats:p>","DOI":"10.3390\/cells15181716","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"1716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting NCAM1\/FGFR1 Signaling to Alleviate Sleep Disturbance-Induced Neuroinflammation in the Hypothalamus"],"prefix":"10.3390","volume":"15","author":[{"given":"Yanxiang","family":"Qu","sequence":"first","affiliation":[{"name":"Department of Pathology and Forensics, Dalian Medical University, Dalian 116044, China"},{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, 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