Role of lactic acid-mediated ALKBH5 in depression induced by blue light exposure at night

Artificial light at night (ALAN) has been classified as a significant environmental endocrine disruptor. Excessive exposure to ALAN has associated with an increased risk of depression. With the extensive use of high-density blue light LED screens, the risk of blue light exposure at night has increased. Animal studies have suggested a close relationship between blue light and depression, but the research on human population is limited. The mechanisms linking blue light to depression require in-depth investigation. We investigated whether nighttime artificial blue light exposure (NABLE) serves as a potential independent risk factor for depression and explored its underlying molecular mechanisms. A case-control study demonstrated that prolonged nighttime device use (> 4 h), high blue-light display patterns, and the use of nightlights during sleep were significantly associated with depressive symptoms in adolescents. This association was independent of demographic and sleep-related factors. Machine learning analyses confirmed these exposures as key predictors of depression. Our previous experimental work demonstrated that blue light exposure during sleep (BLS) induced depression-like behaviors in rodents. Building upon this, we have now reported that BLS elevates lactic acid levels in the lateral habenula (LHb), which upregulates the RNA demethylase ALKBH5 and modifies N⁶-methyladenosine (m⁶A) level. This cascade disrupts neuronal plasticity and induces depression-like phenotypes. Further validating the mechanism, LHb-specific ALKBH5 knockdown reduced both behavioral and synaptic abnormalities, while peripheral blood samples from adolescents with high NABLE exposure exhibited increased Alkbh5 expression. In conclusion, our findings indicate that NABLE is significantly associated with adolescent depression. The identified lactic acid-ALKBH5-m⁶A axis correlates environmental light exposure with neuroplasticity and mood regulation. These findings provide mechanistic insight into environmentally light-associated depression and highlight the significance of managing nocturnal blue light exposure as a potential preventive strategy for adolescent mental health.