Anwulignan mitigates UVB-induced skin photodamage by dual activation of the Nrf2/PINK1/Parkin and Nrf2/SLC7A11/GPX4 signaling pathways.

BACKGROUND

Skin photoaging (SP) is a major contributor to skin aging. Anwulignan (AN) has been confirmed to possess diverse biological activities. This study investigated the protective effect of AN against SP and explored its underlying mechanisms.

METHODS

A UVB-induced SP model in mice was established to evaluate skin erythema index (EI), transepidermal water loss (TEWL), and skin hydration. Histopathological assessments were performed using hematoxylin and eosin (HE), Masson, and Sirius red staining. Transmission electron microscopy examined the morphology and quantity of mitochondria in epidermal cells. ELISA measured levels of hydroxyproline (HYP), hyaluronic acid (HA), oxidative stress markers, and inflammation indicators. Molecular docking predicted the potential targets of AN on UVB-induced SP. Western blot and immunofluorescence staining assessed the expression of proteins related to oxidation, inflammation, aging, ferroptosis, and autophagy. Zebrafish experiments further validated the effects.

RESULTS

AN significantly alleviated SP, evidenced by increased levels of HA and HYP, suppressed pro-inflammatory cytokine expression, reduced reactive oxygen species (ROS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and malondialdehyde (MDA), while enhancing activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). It also regulated the expression of proteins involved in the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis. Significant differences were observed among groups in tail fin area, β-galactosidase staining fluorescence intensity, yolk sac fluorescence, and mitochondrial fluorescence in muscle.

CONCLUSION

AN may exert protective effects against SP by targeting Nrf2 and subsequently activating both the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis.