Propofol addiction drives neuronal senescence and cognitive decline via autophagy-mediated ADAR1/SIRT1 disruption.

Propofol addiction represents a significant clinical challenge with no approved pharmacotherapy. While cognitive decline is a hallmark of substance use disorders, its underlying mechanisms in propofol addiction remain unclear. This study investigates whether propofol abuse induces neuronal senescence and cognitive impairment and explores the involved molecular pathways. We found that propofol administration in mice led to significant learning and memory deficits, which were associated with p16(INK4a)-dependent neuronal senescence in the hippocampus. Knockdown of p16(INK4a) alleviated both senescence and cognitive decline. Mechanistically, propofol triggered autophagic degradation of ADAR1 via LC3-binding motifs, leading to reduced SIRT1 expression and subsequent upregulation of p16(INK4a). Both neuronal-specific and systemic inhibition of autophagy attenuated propofol-induced senescence, cognitive impairment, and addictive behaviors. Our findings reveal a novel ADAR1-SIRT1- p16(INK4a) pathway mediated by autophagy in propofol addiction, suggesting that targeting autophagy or senescence may offer therapeutic strategies for treating propofol use disorder.