Tea Polyphenol EGCG Prevents UVB-Induced Oxidative Stress via SIRT3-Mediated Activation of SOD2: Mechanistic Insights from Molecular Interactions

Abstract UVB irradiation triggers skin photodamage via oxidative stress and mitochondrial dysfunction. This study investigated the photoprotective mechanism of EGCG, the most abundant polyphenol in green tea, in HaCaT keratinocytes. EGCG pretreatment attenuated UVB-induced viability loss and oxidative stress, evidenced by reduced 4-hydroxy-2-nonenal, protein carbonyls, and ROS, alongside restored glutathione redox balance. EGCG recovered SIRT3 enzymatic activity without affecting its expression and promoted SOD2 deacetylation at Lys68 and Lys122 in vitro. SPR and ITC confirmed direct, high-affinity binding of EGCG to SIRT3, with molecular dynamics simulations revealing a stable complex. EGCG also enhanced the binding affinity between SIRT3 and its acetylated p53 substrate in vitro. Critically, pharmacological inhibition of SIRT3 by 3-TYP abolished EGCG’s protective effects, supporting a critical role of SIRT3 in EGCG-mediated protection. Collectively, these findings indicate that EGCG protects against UVB-induced skin photodamage by binding to and activating SIRT3, thereby promoting SIRT3-mediated SOD2 deacetylation to alleviate oxidative stress.