Cornus officinalis Fruit Extract as an AMPK-Associated Mitochondrial Bioenergetic Modulator in Skin Aging Models

Background: Mitochondrial dysfunction is a fundamental driver of skin aging, making the enhancement of cellular bioenergetics an important strategy in dermocosmetic innovation. Cornus officinalis fruit extract (COFE), standardized for iridoid glycosides, was investigated for its ability to modulate mitochondrial function and counteract photo-oxidative stress associated with skin aging. Methods: Human dermal fibroblasts were treated with COFE to evaluate mitochondrial bioactivation. Transcriptomic changes were assessed using RNA sequencing (RNA-seq), with key mitochondrial genes validated by qPCR. AMPK phosphorylation, intracellular ATP content, NAD+/NADH ratio, and mitochondrial membrane potential (ΔΨm) were quantified as functional indicators of mitochondrial performance. To examine anti-aging relevance, a reconstructed human epidermis model was challenged with UVA and retinol to induce photo-oxidative stress. COFE’s effects on inflammatory (IL-1α), hydration (AQP3), proliferation (Ki67), and barrier-related (PKCα) markers were subsequently analyzed. Results: COFE was associated with activation of AMPK signaling and coordinated upregulation of OXPHOS-related genes in dermal fibroblasts, increasing ATP by 30.00%, the NAD+/NADH ratio by 158.71%, and ΔΨm by 158.82%. It also reduced IL-1α and upregulated AQP3, Ki67, and PKCα in a UVA/retinol-challenged epidermis model. In vivo, a 1% COFE eye cream produced statistically significant improvements across hydration, barrier function, redness, skin tone, wrinkles, elasticity, and periorbital contour after 28 days. Conclusions: COFE functions as an AMPK-associated mitochondrial bioenergetic modulator that enhances cellular energy metabolism and mitigates photo-oxidative stress in skin-relevant experimental models. The concordance between mechanistic findings and clinical outcomes supports COFE as a promising anti-aging active ingredient for dermocosmetic applications.