Ganoderic Acid A Mitigates Sleep Deprivation-Induced Behavioral Deficits and Aging-like Phenotypes by Cryptochrome 1-Mediated Suppression of Ferroptosis and Pyroptosis

Sleep deprivation (SD) is closely linked to affective disorders, cognitive impairment, and accelerated neuroaging. Using an SD mouse model, we examined the neuroprotective effects of Ganoderic acid A (GAA), focusing on ferroptosis, pyroptosis, and their potential regulation by Cryptochrome 1 (Cry1). GAA significantly ameliorated SD-induced affective deficits, cognitive decline, and aging-like phenotypes. Mechanistically, GAA reversed SD-induced dysregulation of ferroptosis-related proteins (SLC7A11, GPX4, and ACSL4, etc.), and concurrently suppressed pyroptosis by inhibiting the NLRP3-caspase-1-GSDMD signaling cascade. Notably, GAA significantly upregulated Cry1 expression, and the protective effects of GAA were substantially diminished in Cry1-deficient mice. Furthermore, surface plasmon resonance and molecular dynamics simulations demonstrated a stable interaction between GAA and Cry1, which may underlie the GAA-induced upregulation of Cry1. Collectively, these findings suggest that Cry1 is involved in the regulation of GAA-associated protective effects against SD-induced neurobehavioral disturbances and neuroaging via suppression of ferroptosis and pyroptosis.