Regulation of melanogenesis via ubiquitin-proteasome system and autophagy by 3,3,5-trimethylcyclohexyl succinate dimethylamide and tranexamic acid.

IF 4.6

Journal of dermatological science Pub Date : 2025-09-26 DOI:10.1016/j.jdermsci.2025.09.004

Jing Wang, Fanglan Zha, Simin Lin, Yun Wei, Lingling Xuan, Zhangying Ye, Hu Huang

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引用次数: 0

Abstract

Background: Excessive melanogenesis in skin melanocytes results in hyperpigmentation disorders.

Objective: This study investigates the combined effects and mechanisms of 3,3,5-trimethylcyclohexanol succinate dimethylamide (335, a succinic acid derivative) and tranexamic acid (TXA) on melanogenesis.

Methods: Skin penetration of 335 was assessed via Raman spectroscopy. Interactions between 335 and TXA were predicted by molecular docking. The anti-melanogenic effect was evaluated by measuring melanin content in human keratinocytes (HaCaT) and mouse melanoma cells (B16). Transcriptome sequencing was performed to identify key pathways by which 335 regulates melanogenesis. Melanosomes were isolated from human melanoma cells (MNT-1) and co-cultured with keratinocytes to validate the specific mechanisms. A 3D melanin skin model was established to evaluate the anti-pigmentation effect of 335 and TXA by analyzing apparent chroma, lightness (L*), and melanin content and distribution.

Results: The skin penetration of 335 was enhanced by the addition of TXA, and the two compounds exhibited hydrogen bonding and hydrophobic interactions. The combination of 335 and TXA (1:10) significantly reduced the melanin content in B16 cells compared to individual treatments. Transcriptomics revealed 335 modulates the ubiquitin-proteasome system (UPS) and autophagy. Experimental validation confirmed that 335 and TXA combination inhibited melanin production by promoting ubiquitination degradation of tyrosinase and autophagic degradation of melanosomes. In the 3D skin model, the combination enhanced skin brightness (apparent chroma and L* value) and reduced melanin deposition.

Conclusion: The combination of 335 and TXA inhibits melanogenesis by UPS-mediated tyrosinase degradation and autophagy-driven melanosome degradation, offering a promising strategy for hyperpigmentation treatment.

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3,3,5-三甲基环己基琥珀酸二甲酰胺和氨甲环酸通过泛素-蛋白酶体系统和自噬调节黑色素生成。

背景：皮肤黑色素细胞过度黑色素生成导致色素沉着症。目的：研究琥珀酸衍生物3,3,5-三甲基环己醇琥珀酸二甲酰胺（335）和氨甲环酸（TXA）对黑色素形成的联合作用及其机制。方法：采用拉曼光谱法测定335例患者的皮肤穿透性。通过分子对接预测了335与TXA之间的相互作用。通过测定人角质形成细胞（HaCaT）和小鼠黑色素瘤细胞（B16）中的黑色素含量来评价其抗黑素生成作用。转录组测序鉴定了335调节黑色素形成的关键途径。从人黑色素瘤细胞（MNT-1）中分离黑色素小体，并与角质形成细胞共培养以验证其特异性机制。建立3D黑色素皮肤模型，通过分析表观色度、亮度（L*）、黑色素含量及分布，评价335和TXA抗色素沉着作用。结果：加入TXA后，335的皮肤渗透性增强，两种化合物表现出氢键和疏水相互作用。与单独处理相比，335和TXA（1:10）的组合显著降低了B16细胞中的黑色素含量。转录组学显示335调节泛素-蛋白酶体系统（UPS）和自噬。实验验证证实335与TXA联合抑制黑色素生成是通过促进酪氨酸酶的泛素化降解和黑色素小体的自噬降解来实现的。在3D皮肤模型中，该组合增强了皮肤亮度（表观色度和L*值），减少了黑色素沉积。结论：335联合TXA通过ups介导的酪氨酸酶降解和自噬驱动的黑素小体降解抑制黑色素生成，为色素沉着症的治疗提供了一种有前景的策略。

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来源期刊

Journal of dermatological science Dermatology

CiteScore

7.60

自引率

0.00%

发文量