Abstract

Background Chronic UVA exposure accelerates photoaging by inducing oxidative stress and mitochondrial dysfunction. Autophagy maintains dermal homeostasis, but its decline promotes aging. Afzelin, a flavonoid with antioxidant activity, has not been fully studied for its autophagy-related photoprotective effects. Purpose To determine whether afzelin protects against UVA-induced photoaging through autophagy and mitophagy activation, and to assess its synergy with ganoderic acid A (GAA), a triterpenoid possessing established anti-aging activity. Methods UVA-irradiated and D-galactose–induced senescence models of human dermal fibroblasts were examined by Western blotting, immunofluorescence, and flow cytometry. A 20-day UVA mouse model evaluated topical efficacy. Synergy was calculated using the Bliss model. Results Afzelin restored UVA-impaired cell viability and reduced β-galactosidase, p53, and p21 while recovering Lamin B1. It lowered ROS levels and restored mitochondrial membrane potential (2.8-fold) via AMPK–AKT/mTOR–ULK1 and PINK1–Parkin activation. Combined with GAA (50 mM), afzelin showed strong synergy (Bliss = 67.6 ± 5.1). In vivo , co-treatment reduced epidermal thickness (∼37.3%), restored collagen I and elastin, and suppressed p53/p21 expression. Conclusion Afzelin alleviates UVA-induced photodamage by activating autophagy and mitophagy. Together with the anti-aging triterpenoid GAA, it exerts synergistic anti-photoaging effects, supporting its potential as a natural autophagy-targeting agent for skin rejuvenation.