Enhanced Extracellular Matrix Synthesis–Related Responses Induced by Ubiquinol‐10 Derivatives in Human Dermal Fibroblasts

ABSTRACT

Skin aging is characterized by impaired extracellular matrix (ECM) synthesis and increased inflammatory signaling in dermal fibroblasts. Notably, ubiquinol‐10 (UqH‐10), the reduced form of coenzyme Q10 (ubiquinone‐10, Uq‐10), supports mitochondrial function and reduces oxidative stress, but its dermal levels decrease with aging. The topical efficacy of UqH‐10 is limited by its physicochemical properties, including oxidative instability, photo instability, and phototoxicity. This study aimed to evaluate the anti‐aging potential of esterified UqH‐10 derivatives—UqH 1,4‐bis‐hemi‐succinate (UqH‐SUC) and UqH 1,4‐bis‐hemi‐glutarate (UqH‐GLUT)—in human dermal fibroblasts. Normal human dermal fibroblasts (NHDFs) were treated with Uq‐10, UqH‐10, or their derivatives (100 μM) for 48 h. Intracellular Uq‐10 and UqH‐derivatives were quantified by LC–MS/MS, while ATP levels and viability were measured using luminescence‐ and fluorescence‐based assays. Gene and protein expression of ECM components, matrix metalloproteinases (MMP1, MMP3), and SASP markers (IL6, IL8, p21) were analyzed by qPCR, ELISA, western blotting, and immunofluorescence. Additional experiments were conducted in the presence of an ascorbic acid derivative to evaluate pro‐COL1A1 production. We found that UqH‐SUC markedly increased intracellular Uq‐10 and UqH‐10 (2.1‐fold vs. Uq‐10; 8.3‐fold vs. UqH‐10), enhanced ATP production, suppressed SASP factors, and upregulated ECM components including COL1A1, elastin, and hyaluronic acid. Despite its minimal conversion to UqH‐10, UqH‐GLUT accumulated intracellularly, reduced SASP expression, and downregulated MMPs. Co‐treatment with UqH‐SUC and phosphorylated ascorbic acid derivatives significantly enhanced extracellular COL1A1 secretion while lowering intracellular retention. Moreover, esterified UqH‐10 derivatives, particularly UqH‐SUC, enhance mitochondrial function, modulate fibroblast senescence, and stimulate ECM synthesis. Moreover, their combination with ascorbic acid derivatives provides a promising strategy for skin anti‐aging intervention.