Oxidative Stress Induces Skin Pigmentation in Melasma by Inhibiting Hedgehog Signaling

Area of Science:

• Dermatology
• Molecular Biology
• Cell Biology

Background:

• Oxidative stress is implicated in melasma pathogenesis.
• Primary cilia may inhibit melanogenesis.
• The interplay between oxidative stress, cilia, and melasma is not fully understood.

Purpose of the Study:

• To investigate the link between oxidative stress, skin hyperpigmentation, and primary cilia in melasma.
• To examine the expression of NRF2, IFT88, and GLIs in melasma.
• To explore the roles of NRF2, IFT88, and GLIs in ciliogenesis and pigmentation.

Main Methods:

• Compared NRF2, IFT88, and GLI expression in melasma lesional and non-lesional skin.
• Utilized cultured human keratinocytes (with/without melanocytes) to study NRF2, IFT88, and GLI roles.
• Performed gene knockdown experiments and utilized specific agonists and chelators.

Main Results:

• Decreased NRF2, HO-1, IFT88, and GLIs were observed in melasma lesional skin.
• NRF2 knockdown reduced IFT88, GLI1, and cilia formation, while increasing PAR2, K10, involucrin, tyrosinase, and melanin.
• These effects were reversed by a smoothened agonist, with calcium modulating some pathways.

Conclusions:

• Oxidative stress in NRF2-downregulated melasma keratinocytes inhibits ciliogenesis.
• This inhibition promotes keratinocyte differentiation, leading to increased melanin synthesis and melanosome transfer.
• Findings suggest a novel mechanism for melasma pathogenesis involving oxidative stress and primary cilia dysfunction.