The study investigates the role of p300 nucleocytoplasmic shuttling in regulating mTORC1 activity and autophagy. p300, a histone acetyltransferase, is crucial for mTORC1 regulation, which is negatively regulated by nutrient deprivation. AMP-activated protein kinase (AMPK) phosphorylates p300 at serine 89, promoting its nuclear import and reducing mTORC1 activity. Protein phosphatase 2A (PP2A) dephosphorylates p300, enabling its export to the cytoplasm and mTORC1 reactivation. This process is disrupted in Hutchinson–Gilford progeria syndrome (HGPS), where progerin mislocalizes p300, activates mTORC1, and inhibits autophagy. Modulating p300 shuttling normalizes these defects, suggesting a therapeutic target for HGPS.The study investigates the role of p300 nucleocytoplasmic shuttling in regulating mTORC1 activity and autophagy. p300, a histone acetyltransferase, is crucial for mTORC1 regulation, which is negatively regulated by nutrient deprivation. AMP-activated protein kinase (AMPK) phosphorylates p300 at serine 89, promoting its nuclear import and reducing mTORC1 activity. Protein phosphatase 2A (PP2A) dephosphorylates p300, enabling its export to the cytoplasm and mTORC1 reactivation. This process is disrupted in Hutchinson–Gilford progeria syndrome (HGPS), where progerin mislocalizes p300, activates mTORC1, and inhibits autophagy. Modulating p300 shuttling normalizes these defects, suggesting a therapeutic target for HGPS.