Manifold hepatoprotective actions of α-lipoic acid on metabolic function through redox regulation, inflammatory modulation, and anti-apoptosis after chronic sleep-deprived injury

Objective: Chronic sleep deprivation (CSD) is a major public health issue that causes metabolic dysfunction by disrupting redox homeostasis and triggering hepatic inflammation. Given the strong anti-oxidative and anti-inflammatory properties of alpha lipoic acid (ALA), this study aims to determine whether exogenous ALA supplementation would provide hepatoprotection and therefore, maintain the metabolic activity following CSD. Methods: Adult male Wistar rats were randomly assigned to three groups (n = 6/group). The first two groups underwent three cycles of 5-day total sleep deprivation followed by 2-day rest, receiving daily 2 mL olive oil (CSD group) or ALA (100 mg/kg in 2 mL olive oil) (CSD + ALA group), respectively. The third group received no treatment serving as yoked control (CSC group). Spectrometric, biochemical, immunoblot, and immunohistochemical analyses were performed to assess the hepatic redox-active Fe2+ intensity, metabolic function, anti-oxidative enzyme expression, and the pro-inflammatory cytokine levels. Results: ALA significantly improves metabolic function as effectively attenuates serum concentrations of AST, ALT, and ALP, and stabilize hepatic Fe2+ intensity. ALA also remarkably decreases the protein level of inflammatory factors including NF-κB, TNF-α, IL-6, IL-1β, and cyclooxygenase-2 (COX2), as well as increases the expression of Nrf2-induced antioxidative enzymes such as SOD1 and glutathione peroxidase (GPx). Moreover, ALA further suppresses apoptosis and ferroptosis by modulating related markers including BAX, Bcl-2, GPx4, and FACL4 activities. Conclusion: These findings clearly demonstrate that ALA confers manifold hepatoprotective effects against CSD-induced dysfunction by significantly restoring redox balance, decreasing hepatic inflammation, suppressing apoptotic and ferroptotic signaling, thereby successfully preserving metabolic activity.