Subcellular photoprotection through precision nutraceuticals: Divergent actions of rutin and punicalagin on redox and mitochondrial homeostasis in human dermal fibroblasts

Excessive ultraviolet A (UVA) exposure is a major environmental factor contributing to skin photoaging and oxidative damage. Identifying natural compounds that can counteract these effects is increasingly relevant for preventive and personalized healthcare. Precision nutrition uses diet-derived bioactives to modulate molecular pathways in defined cellular contexts. Polyphenols are promising for sustaining redox and metabolic balance under stress. This study examined the photoprotective actions of rutin (buckwheat, citrus peel) and punicalagin (pomegranate) in human dermal fibroblasts exposed to UVA radiation. Phasor-based fluorescence lifetime imaging microscopy (FLIM) quantified lipid peroxidation-related oxidative stress (F_ox) and oxidative phosphorylation activity (F_oxphos). Mitochondrial morphology was assessed via fission (Fis1) and fusion (MFN2) markers. Though UVA exposure tended to increase oxidative stress, the observed variation is not significant. Rutin provided superior antioxidant protection under UVA stress, substantially reducing F_ox to 0.129 ± 0.02 with a near-significant trend, while punicalagin demonstrated stronger baseline antioxidant activity. Both compounds enhanced oxidative phosphorylation under stress: punicalagin increased F_oxphos to 0.823 ± 0.02 (p = 0.004 vs UVA) and rutin to 0.789 ± 0.02 (p = 0.023 vs UVA). UVA disrupted mitochondrial networks, elevating fission and reducing fusion. Rutin reversed these effects, restoring fusion and reducing fission, whereas punicalagin provided partial recovery. In summary, rutin offered broader cytoprotection by mitigating oxidative stress and preserving mitochondrial integrity, while punicalagin mainly supported metabolic activity. These distinct responses highlight polyphenol-based nutraceuticals as precision tools for targeted skin photoprotection, suggesting their potential use in dietary or topical formulations to counteract everyday UVA exposure and photoaging.