Multitargeted Modulation of Skin Dullness by HNHT Formulation: Synergistic Inhibition of Melanogenesis, Glycation, and Lipofuscin Deposition

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BACKGROUND: Skin dullness, characterized by pigmentation disorders and yellowing, is a major cosmetic concern in Asian populations. Lipofuscin exhibits ultraviolet (UV)/visible light spectral absorption, reduces skin reflectance, and contributes to dullness, whereas existing therapies targeting melanogenesis and glycation lack comprehensive efficacy. This study aimed to evaluate the multimodal anti-dullness effects of a novel formulation (HNHT: hyaluronic acid, niacinamide, hydrolyzed red algae, and tranexamic acid). METHODS: In vitro models (melanocytes, keratinocytes, fibroblasts, ex vivo skin model, and three-dimensional (3D) skin models) were used to assess melanin regulation, glycation inhibition, and lipofuscin clearance. RESULTS: In ultraviolet B (UVB)-exposed 3D skin models, 12.5% HNHT significantly improved skin color, appearance, and brightness (8.44% increase in L* value) and reduced melanin content (12.5% inhibition). Then, 12.5% HNHT downregulated the expression of key melanogenic genes (TYR and MITF; p < 0.001) in melanocytes and decreased UVB-induced α-melanocyte-stimulating hormone secretion in keratinocytes (2867.78 versus 3444.72 pg/mL; p < 0.05). The formulation enhanced melanosome clearance through autophagy activation (174% LC3-II increase, 80% GP100 reduction; p < 0.01) and boosted antioxidant capacity via Nrf2 activation and reactive oxygen species reduction (p < 0.05). In glycation, 50% HNHT upregulated anti-glycation enzymes (GLO1, GLO2, and GPX1) and reduced carboxymethyllysine (CML) by 23.16% in fibroblasts (p < 0.01), while 100% HNHT decreased CML by 34.93% in ex vivo skin model. Furthermore, 50% HNHT suppressed hydrogen peroxide-induced lipofuscin accumulation by 52.20% (p < 0.01). CONCLUSIONS: These findings highlight HNHT as a multitargeted therapeutic agent that alleviates skin dullness through melanogenesis inhibition, enhances melanosome degradation, suppresses glycation, mitigates oxidative stress, and promotes lipofuscin clearance, thereby establishing a novel therapeutic paradigm against solar radiation-induced hyperpigmentation and skin yellowing.

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