Molecular Signatures of Ferroptosis in Sleep Disorders: A Comparative Analysis of GPX4, ACSL4, and TfR1

Recent research has shown the complex relationship between sleep and cellular death pathways. Ferroptosis is an iron-dependent form of regulated cell death associated with several neurodegenerative disorders. This process is regulated by key molecular markers: Glutathione peroxidase 4 (GPX4) acts as a primary defense against oxidative stress-induced ferroptosis, whereas acyl-CoA synthetase long-chain family member 4 (ACSL4) has been implicated in lipid peroxidation processes. This study evaluates ferroptosis-associated markers in individuals with sleep disorders to investigate potential alterations in ferroptosis-related pathways. We enrolled 86 patients (24 with obstructive sleep apnea syndrome, 21 with restless legs syndrome, 21 with narcolepsy, and 22 with insomnia) and 19 healthy controls. mRNA expression levels of GPX4 and ACSL4 were analyzed by real-time PCR, while protein levels were quantified via Western blotting and ELISA (GPX4). GPX4 mRNA and protein levels were significantly lower in the RLS, insomnia, and narcolepsy groups than in controls (p < 0.001), suggesting altered antioxidant defense mechanisms. However, this reduction was not significant in OSAS. Conversely, while ACSL4 mRNA expression was lower in RLS, insomnia, and narcolepsy, ACSL4 protein levels were significantly elevated (p < 0.001), indicating discrepancies between gene and protein expression patterns. The concurrent reduction in GPX4 and increased ACSL4 protein expression observed across several sleep disorder groups may reflect alterations in ferroptosis-associated molecular signatures. This study represents one of the first human investigations exploring this relationship; our findings suggest possible alterations in ferroptosis-associated molecular pathways in sleep disorders. Although the physiological relevance of sleep is well-established, the molecular pathways linking sleep disruptions to cellular dysfunction remain poorly understood. This study provides some of the first human data evaluating ferroptosis-associated molecular alterations across major sleep disorders, including OSAS and RLS. Our findings revealed reduced GPX4 expression and altered ACSL4 expression patterns, suggesting possible changes in cellular homeostasis and antioxidant defense mechanisms. These findings provide new insights into the molecular mechanisms potentially involved in sleep disorders and suggest possible associations between ferroptosis-related pathways and sleep-related cellular dysfunction beyond general oxidative stress. Consequently, our findings may contribute to future investigations exploring ferroptosis-associated pathways as potential biomarkers or therapeutic targets in sleep medicine.