Sleep restriction and deprivation are highly prevalent in modern society and are associated with systemic health risks. However, the molecular basis distinguishing reversible from long-lasting transcriptomic effects of insufficient sleep remains poorly understood. In this study, we systematically investigated the transcriptomic impacts of one-week sleep restriction (SR-1wk), two-week sleep restriction (SR-2wk), subsequent five-week recovery sleep (SR-recovery), and chronic sleep deprivation (SD) in in healthy adult males. Whole-blood RNA sequencing and temporal expression profiling identified two distinct gene groups: 74 genes exhibiting persistent dysregulation even after 5 weeks of recovery sleep, and 68 genes demonstrating complete restoration. Functional annotation revealed that recovery-associated genes were enriched in immune rebalancing, metabolic adaptation, and epigenetic regulation, whereas not fully recovered within the study timeframe genes were predominantly linked to inflammation, ribosomal activity, and poorly characterized molecular networks. Additionally, we uncovered 59 uncharacterized transcripts, including antisense RNAs, novel lncRNAs, and miRNAs, which may represent previously unrecognized regulatory pathways in sleep biology. Our findings suggest that recovery sleep alone cannot fully reverse the molecular scars induced by prolonged sleep restriction. The contrast between recoverable and not fully recovered within the study timeframe genes highlights both the adaptive and vulnerable aspects of biological systems under sleep loss. Our findings provide a basis for identifying biomarkers of chronic sleep debt and highlight targeted interventions-such as anti-inflammatory, circadian, and antioxidant strategies-as potential means to mitigate long-term risks. At the same time, they establish a foundation for future functional studies to uncover novel mechanisms of sleep-related pathophysiology.
Cheng et al. (2026) studied this question.