Camellioside A Engages SIRT3 to Promote FOXO3-PINK1/Parkin Dependent Mitophagy and Attenuate UVB-Induced Skin Photoaging

ABSTRACT Chronic ultraviolet B (UVB) irradiation is a principal driver of skin photoaging, characterized by oxidative stress, mitochondrial dysfunction, fibroblast senescence, and extracellular matrix degradation. Although Camellia chekiangoleosa shows potential for anti-photoaging applications, its bioactive constituents and underlying mechanisms remain poorly defined. Herein, we identified camellioside A (CA) as the key bioactive constituent responsible for the anti-photoaging efficacy of C. chekiangoleosa . In UVB-stressed human foreskin fibroblasts (HFFs) and NIH-3T3 cells, CA markedly attenuated cellular senescence, restored mitochondrial redox homeostasis, and improved mitochondrial quality control by potentiating PINK1/Parkin-mediated mitophagy. Mechanistically, CA directly engaged and activated the mitochondrial deacetylase SIRT3, with Gln228 being critical for CA-SIRT3 engagement and downstream activity. SIRT3 activation promoted FOXO3 deacetylation at Lys271 and subsequent nuclear translocation, whereas mutation of SIRT3 Gln228 impaired these effects. Mutation of FOXO3 Lys271 further supported the functional importance of this site in CA-mediated FOXO3 deacetylation and nuclear localization. Promoter occupancy and dual-luciferase reporter assays demonstrated that activated FOXO3 enhanced PINK1 transcription through an AAACA-containing responsive element at -550 to -546 bp of the PINK1 promoter. In a chronic UVB-induced photoaging mouse model, topical CA significantly ameliorated wrinkle formation, dermal structural damage, and extracellular matrix remodeling, whereas AAV9-mediated Sirt3 knockdown substantially attenuated these protective effects and disrupted FOXO3-PINK1 signaling and mitophagy. Collectively, these findings identify CA as a key anti-photoaging constituent of C. chekiangoleosa and establish a SIRT3-FOXO3-PINK1 signaling axis that couples SIRT3 activation to mitochondrial quality control during UVB-induced skin photoaging.