Abstract

The molecular mechanisms by which silent information regulator 1 (SIRT1) protects against skin photoaging remain incompletely defined. This study demonstrates that repetitive ultraciolet A (UVA) irradiation downregulates both SIRT1 and its transcription factor target FOXO3a in human skin and dermal fibroblasts (HDFs), establishing a chronic oxidative stress and senescence model. We found that pharmacological activation of SIRT1 with SRT1720 significantly mitigated UVA-induced damage, reducing oxidative stress, DNA damage (8-OHdG), cellular senescence, and extracellular matrix degradation. Mechanistically, SIRT1 deacetylated and stabilized Forkhead box O3 (FOXO3a), enabling it to transcriptionally upregulate key antioxidant defense genes (SOD2, HO-1, CAT). Crucially, all protective effects of SIRT1 activation were completely abolished upon FOXO3a knockdown, genetically establishing FOXO3a as the essential downstream effector. Our results delineate the SIRT1-FOXO3a deacetylation axis as a central regulatory pathway that coordinates antioxidant defense and ECM homeostasis, highlighting its potential as a precise therapeutic target for mitigating skin photoaging.