Yu Bo-Yeong, Ngo Hoang Hai, Choi Won Jun, Keum Young-Sam
College of Pharmacy and Integrated Research, Institute for Drug Development, Dongguk University, 32 Dongguk-ro, Goyang 10326, Gyeonggi-do, Republic of Korea.
Antioxidants (Basel). 2023 Mar 10;12(3):692. 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.
衣康酸是巨噬细胞受到细胞内或细胞外刺激时产生的一种代谢产物，用于对抗和消除促炎反应。在本研究中，我们观察到二甲基衣康酸（DMI）抑制B16F10细胞中的黑色素生成。DMI抑制小眼相关转录因子（MITF），并下调MITF靶基因的表达，如酪氨酸酶（TYR）、酪氨酸酶相关蛋白1（TRP-1）和酪氨酸酶相关蛋白2（TRP-2）。DMI还降低了黑皮质素1受体（MC1R）的水平和α-促黑素细胞激素（α-MSH）的产生，导致细胞外信号调节激酶1/2（ERK1/2）和MITF活性受到抑制。构效关系（SAR）研究表明，DMI中的α,β-不饱和羰基部分是靶向类 Kelch 样 ECH 相关蛋白 1（KEAP1）以激活核因子 E2 相关因子 2（NRF2）所必需的部分，是抑制黑色素生成所必需的，敲低 Nrf2 可减弱 DMI 对黑色素生成的抑制作用。总之，我们的研究表明，由 KEAP1-NRF2 途径调节的 MC1R-ERK1/2-MITF 轴是 DMI 抑制黑色素生成的分子靶点。
