AbstractSleep behavior is conserved throughout evolution, and sleep disturbances are a frequent comorbidity of neuropsychiatric disorders. However, the molecular basis underlying sleep dysfunctions in neurological diseases remains elusive. Using a model for neurodevelopmental disorders (NDDs), theDrosophila Cytoplasmic FMR1 interacting proteinhaploinsufficiency (Cyfip^85.1/+), we identify a mechanism modulating sleep homeostasis. We show that increased activity of the sterol regulatory element-binding protein (SREBP) inCyfip^85.1/+flies induces an increase in the transcription of wakefulness-associated genes, such as the malic enzyme (Men), causing a disturbance in the daily NADP⁺/NADPH ratio oscillations and reducing sleep pressure at the night-time onset. Reduction in SREBP or Men activity inCyfip^85.1/+flies enhances the NADP⁺/NADPH ratio and rescues the sleep deficits, indicating that SREBP and Men are causative for the sleep deficits inCyfipheterozygous flies. This work suggests modulation of the SREBP metabolic axis as a new avenue worth exploring for its therapeutic potential in sleep disorders.