Abstract
Chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA), is strongly implicated in the development of hepatic injury. However, the cellular mechanisms underlying CIH-induced liver dysfunction remain poorly understood. This study aimed to systematically characterize hepatic cellular responses to CIH at single-nucleus resolution. A rodent model of CIH was established and subjected to histological and transcriptomic analyses. Single-nucleus RNA sequencing (snRNA-seq) was performed to delineate transcriptional alterations across liver cell populations. Differentially expressed genes (DEGs) and pathway enrichment analyses were conducted to identify key biological processes and signaling networks affected by CIH exposure. CIH exposure resulted in marked hepatic injury characterized by spotty necrosis and prominent infiltration of inflammatory cells. SnRNA-seq identified ten major liver cell types with stable composition but revealed extensive transcriptional reprogramming across multiple hepatic subpopulations. CIH suppressed PPAR signaling and fatty acid metabolism in hepatocytes and hepatic stellate cells and activated AMPK and PI3K–Akt pathways related to stress response and fibrogenic processes. Mononuclear phagocytes showed upregulation of NF-κB signaling and complement/coagulation cascades. Endothelial cells exhibited changes in genes associated with cytoskeletal organization and tight junctions. T cell subpopulations displayed altered expression of genes involved in metabolic regulation and endoplasmic reticulum stress. This study provides the first single-nucleus transcriptomic atlas of the liver under CIH, revealing cell type–specific molecular remodeling across hepatocytes, stromal, and immune cells. These findings elucidate the complex cellular interplay associated with CIH-induced hepatic injury and offer novel insights into potential therapeutic targets for OSA-related liver dysfunction.
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Data availability
The single-nucleus RNA sequencing datasets generated and analyzed in this study have been deposited in the NCBI Sequence Read Archive (SRA) under accession number PRJNA1345096 and are publicly available at: [https://www.ncbi.nlm.nih.gov/sra/PRJNA1345096](https:/www.ncbi.nlm.nih.gov/sra/PRJNA1345096) .
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Acknowledgements
The authors thank the Singleron Biotechnologies for their help with the single-cell RNA sequencing analysis.
Funding
This work was supported by Natural Science Foundation of Fujian Province (2022J011474), Young people training project from Fujian Province Health Bureau (2022GGA053), and Startup Fund for Scientific Research of Fujian Medical University (2024QH1687), and grant PDA202202 for scientific research of Zhangzhou Affiliated Hospital of Fujian Medical University.
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LDC supervised and designed this project. WSH, CQW, and JFH performed the animal experiment. JML and CDY prepared samples for snRNA-seq. WSH, LDC and LL analyzed the snRNA-seq data. YZH performed pathology analysis. WSH and CQW wrote the manuscript.
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This study was approved by the approved by the Animal Ethics Committee of Fujian Medical University (IACUC FJMU 2022-0031). All methods were carried out in accordance with relevant guidelines and regulations. All methods are also reported in accordance with ARRIVE guidelines.
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Huang, WS., Wang, CQ., Huang, YZ. et al. Single-nucleus RNA sequencing uncovers cell type-specific alterations in OSA-related liver injury. Sci Rep (2026). https://doi.org/10.1038/s41598-026-42236-1
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DOI: https://doi.org/10.1038/s41598-026-42236-1
