Dimethyl Itaconate Inhibits Melanogenesis in B16F10 Cells

• Published in: Antioxidants Vol. 12; no. 3; p. 692
• Main Authors: Yu, Bo-Yeong, Ngo, Hoang Hai, Choi, Won Jun, Keum, Young-Sam
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.03.2023; MDPI
• Subjects: Antibodies; Dehydrogenases; dimethyl itaconate (DMI); Dopachrome isomerase; Extracellular signal-regulated kinase; Inflammation; KELCH-like ECH-associated protein 1 (KEAP1); Macrophages; Melanocortin; melanocortin 1 receptor (MC1R); Melanocyte-stimulating hormone; Melanoma; Metabolites; Microphthalmia-associated transcription factor; microphthalmia-associated transcription factor (MITF); NF-E2-related factor 2 (NRF2); Physiological aspects; Plasmids; Proteins; Radiation; Tyrosinase-related protein 1; South Korea; United States > US; microphthalmia-associated transcription factor (MITF); melanocortin 1 receptor (MC1R); NF-E2-related factor 2 (NRF2); dimethyl itaconate (DMI); KELCH-like ECH-associated protein 1 (KEAP1)
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox12030692

Itaconate is a metabolite produced to counteract and resolve pro-inflammatory responses when macrophages are challenged with intracellular or extracellular stimuli. In the present study, we have observed that dimethyl itaconate (DMI) inhibits melanogenesis in B16F10 cells. DMI inhibits microphthalmia-associated transcription factor (MITF) and downregulates the expression of MITF target genes, such as tyrosinase (TYR), tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2). DMI also decreases the level of melanocortin 1 receptor (MC1R) and the production of α-melanocyte stimulating hormone (α-MSH), resulting in the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and MITF activities. The structure-activity relationship (SAR) study illustrates that the α,β-unsaturated carbonyl moiety in DMI, a moiety required to target KELCH-like ECH-associated protein 1 (KEAP1) to activate NF-E2-related factor 2 (NRF2), is necessary to inhibit melanogenesis and knocking down Nrf2 attenuates the inhibition of melanogenesis by DMI. Together, our study reveals that the MC1R-ERK1/2-MITF axis regulated by the KEAP1-NRF2 pathway is the molecular target responsible for the inhibition of melanogenesis by DMI.