Decoding the Sleep Enigma: A Proteomic Mediation Analysis Linking Healthy Sleep Patterns to Lung Cancer Risk

Study Objectives The biological link between sleep patterns and lung cancer remains an enigma. This study aims to explore how healthy sleep patterns modulate lung cancer risk through proteomic mediation, and develop a sleep-related biomarker panel. Methods This study utilized data from the UK Biobank, comprising 34,881 participants. We used a composite sleep score that considered the following five sleep behaviours sleep duration, chronotype, insomnia, snoring, and daytime sleepiness (0-5 scores). Proteomic profiling measured 2,862 proteins, which were then used to build proteomic signatures through logistic regression to identify significant proteins, followed by LASSO regression to select representative biomarkers for forming weighted signatures. Cox proportional hazards models and mediation analysis were employed to evaluate associations between sleep patterns, proteins, and lung cancer risk. Results Higher healthy sleep scores were significantly associated with reduced lung cancer risk, with hazard ratios (HR = 0.589, p = 0.046) for a score of 3 and (HR = 0.516, p = 0.013) for a score of 4. Similar trends were observed in non-small cell lung cancer (NSCLC) and lung adenocarcinoma. Proteomic signature analysis revealed that protein signatures associated with healthy sleep scores had a protective effect against lung cancer (HR = 0.865, p < 0.001) and NSCLC (HR = 0.863, p < 0.001). Additionally, mediation analysis identified 18 proteins with mediation proportions exceeding 10% in the relationship between healthy sleep scores and lung cancer, with CXCL17 showing the highest mediation proportion. Conclusions This study reveals a potential association between healthy sleep patterns and reduced lung cancer risk.