Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Piperine Regulates Melanogenesis through ERK Activation and Proteasomal Degradation of MITF

  • Jun Hyeong Lee (Department of Genetics and Biotechnology, Graduate School of Biotechnology, College of Life Science, Kyung Hee University) ;
  • Jieun Lee (Department of Genetics and Biotechnology, Graduate School of Biotechnology, College of Life Science, Kyung Hee University) ;
  • Sukanya Dej-adisai (Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University) ;
  • Jae Sung Hwang (Department of Genetics and Biotechnology, Graduate School of Biotechnology, College of Life Science, Kyung Hee University)
  • Received : 2024.04.25
  • Accepted : 2024.06.28
  • Published : 2025.03.01
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Abstract

Melanin is a bio-pigment molecule synthesized by melanocytes. Its role is to shield the skin from ultraviolet radiation. Nonetheless, aberrant melanin production, whether excessive or deficient, can lead to conditions such as vitiligo, freckles, melanocytic nevi, and even melanoma. The biosynthetic pathway of melanin is known as melanogenesis, which is regulated by various transcription factors and enzymatic processes. Piperine (PPN), an alkaloid compound extracted from Piper retrofractum Vahl., was investigated for its potential anti-fungal and anti-inflammatory effects. Our hypothesis centered on the inhibition of melanin biosynthesis in response to PPN treatment. Subsequently, it was observed that PPN treatment resulted in a dose-dependent reduction in melanin production, accompanied by a decrease in tyrosinase activity. Furthermore, PPN was found to downregulate the protein levels of key melanogenesis-related genes. Additionally, PPN was observed to elevate the phosphorylation levels of ERK. To assess the role of ERK signaling in PPN-induced melanogenesis regulation, PD98059, an ERK inhibitor, was used. When Melan-A cells were treated with PD98059, the reduced expression level of MITF and melanin content induced by piperine were restored. Additionally, phosphorylation of ERK increased the phosphorylation of MITF at Ser73. This phosphorylated MITF leads to ubiquitination, and ultimately, the protein level of MITF decreases through proteasomal degradation. Likewise, when Melan-A cells were treated with MG132, a proteasomal inhibitor, the reduced expression level of MITF and melanin content induced by piperine were restored. Consequently, PPN can be a potential candidate for application as a skin whitening agent or in formulations to mitigate hyperpig-mentation.

Keywords

Acknowledgement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HP23C0001).

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