Tang Bingsi, Yu Jiangfan, Tang Rui, He Xinglan, Liu Jiani, Liu Licong, Song Zehong, Shi Yaqian, Zeng Zhuotong, Zhan Yi, Qiu Xiangning, Xiao Yangfan, Ding Yan, Xiao Rong
Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, China.
Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, China.
iScience. 2024 Jul 10;27(8):110483. doi: 10.1016/j.isci.2024.110483. eCollection 2024 Aug 16.
Systemic sclerosis (SSc) is an autoimmune disease affecting multiple tissues. The underlying causes and mechanisms of subcutaneous adipose tissue (SAT) loss in SSc remain unclear. Recent studies have highlighted the role of microRNAs in adipogenesis. Our study found that miR-4769-3p was upregulated in SSc patients and its silencing promoted SAT recovery in bleomycin-induced SSc mice, suggesting that miR-4769-3p might affect adipogenesis in SSc. Manipulating miR-4769-3p expression in 3T3-L1 cells revealed that its inhibition enhanced adipogenesis, while its overexpression weakened it. Further investigations showed that miR-4769-3p bound to 3'UTR of ubiquitin-specific protease-18 (USP18), inhibiting its expression, while USP18 interacted with voltage-dependent anion channel-2 (VDAC2), both of which were reduced in SSc. Silencing either USP18 or VDAC2 attenuated adipogenesis. Notably, USP18 inhibited VDAC2 ubiquitination and degradation, whereas miR-4769-3p reversed the VDAC2-induced elevation of adipogenesis, suggesting that miR-4769-3p inhibited adipogenesis by negatively regulating the USP18/VDAC2 pathway, providing a potential therapeutic target for SSc.
系统性硬化症（SSc）是一种影响多个组织的自身免疫性疾病。SSc患者皮下脂肪组织（SAT）丢失的潜在原因和机制尚不清楚。最近的研究强调了微小RNA在脂肪生成中的作用。我们的研究发现，miR-4769-3p在SSc患者中上调，其沉默促进了博来霉素诱导的SSc小鼠的SAT恢复，这表明miR-4769-3p可能影响SSc中的脂肪生成。在3T3-L1细胞中操纵miR-4769-3p的表达表明，其抑制增强了脂肪生成，而其过表达则减弱了脂肪生成。进一步的研究表明，miR-4769-3p与泛素特异性蛋白酶-18（USP18）的3'UTR结合，抑制其表达，而USP18与电压依赖性阴离子通道-2（VDAC2）相互作用，这两者在SSc中均减少。沉默USP18或VDAC2均可减弱脂肪生成。值得注意的是，USP18抑制VDAC2的泛素化和降解，而miR-4769-3p逆转了VDAC2诱导的脂肪生成升高，这表明miR-4769-3p通过负调节USP18/VDAC2途径抑制脂肪生成，为SSc提供了一个潜在的治疗靶点。
