Photoaging is responsible for over 80% of skin aging and promotes skin cancer development. Ultraviolet B (UVB) radiation encounters to photoaging through multi-level damage cascades, demanding novel interventions to target its earlier stages. Pomegranate Peel extract (PPE) has powerful photoprotective properties; however, its underlying mechanisms remain largely unexplored, particularly regarding the mechanisms regulating inflammation-mitophagy-senescence balance in photoaging. Moreover, the complexity and large-sized nature of PPE constituents limit its topical efficacy. This study delivers an integrated molecular exploration of the antiphotoaging mechanisms of PPE and optimizes its photoprotective performance through incorporation in a biocompatible bilophytosome. Liquid chromatography-High Resolution Mass Spectrometry (LC-HRMS) was used to characterize PPE constituents. Molecular docking and bioinformatics analyses predicted potential molecular interactions and pathways associated with skin photoaging. Finally, the anti-photoaging mechanisms of crude PPE and PPE-bilophytosome were experimentally investigated in a UVB- induced photoaging animal model. Both PPE and PPE-bilophytsome markedly inhibited extracellular signal-regulated Kinase (ERK) phosphorylation, reducing IL-6, iNOS, and TGFβ1 levels. They significantly downregulated miR-34c and p21 while restoring PTEN-induced kinase 1 (PINK-1) closer to normal ranges, eventually reducing matrix metalloproteinases. Compared to crude PPE, PPE-bilophytosome achieved superior performance in all tested parameters. It restored collagen and normal skin architecture as witnessed by histological examination, due to enhanced permeability as confirmed by confocal microscopy. Our findings demonstrate the powerful pleiotropic modulatory effect of PPE on photoaging key players, that can be further optimized through incorporation in a stable bilosome system.
