Single-Nucleus Transcriptomics Reveals Ubiquitin Pathway Dysregulation and Impaired Neuroglial Communication in Chronic Secondhand Smoke-Induced Cognitive Decline

Chronic exposure to secondhand smoke (SHS) has been epidemiologically associated with cognitive decline and neurodegenerative disease risk; however, the underlying cellular and molecular mechanisms remain unclear. Here, we established a 54-week-old mouse model of long-term SHS exposure and performed behavioral testing, histological analysis, and single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue to comprehensively characterize cellular alterations. SHS-exposed mice exhibited significant impairments in spatial learning and memory, accompanied by neuronal loss in hippocampal subregions. Transcriptomics analysis revealed marked dysregulation of the ubiquitin (Ub)-mediated proteolysis pathway in neurons. Pseudotime trajectory analysis indicated the progressive downregulation of Ubb in astrocytes following SHS exposure. Immunofluorescence staining confirmed decreased Ub levels in both neurons and astrocytes. Cell–cell communication analysis revealed reduced signaling strength between glial cells and neurons, thus indicating disrupted intercellular interactions. Collectively, these findings highlight ubiquitin pathway alterations and impaired glia–neuron communication as key pathological features of SHS-induced cognitive deficits, thereby providing new mechanistic insights into how chronic environmental toxicant exposure may contribute to neurodegeneration.