Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy. However, its mechanism of action remains elusive. Here, we performed chemoproteomics-aided target deconvolution of lipoic acid and its active close analog lipoamide. We find that histone deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are molecular targets of the reduced form of lipoic acid and lipoamide. Importantly, only the naturally occurring (R)-enantiomer inhibits HDACs at physiologically relevant concentrations and leads to hyperacetylation of HDAC substrates. The inhibition of HDACs by (R)-lipoic acid and lipoamide explain why both compounds prevent stress granule formation in cells and may also provide a molecular rationale for many other phenotypic effects elicited by lipoic acid.

硫辛酸是中央代谢途径中必需的酶辅因子。由于其声称的抗氧化特性，外消旋 ( R / S )-硫辛酸被用作食品补充剂，但也作为药物在涵盖多种疾病的 180 多项临床试验中得到研究。此外，( R / S )-硫辛酸是批准用于治疗糖尿病神经病变的药物。然而，其作用机制仍然难以捉摸。在这里，我们对硫辛酸及其活性紧密类似物硫辛酰胺进行了化学蛋白质组学辅助的靶解卷积。我们发现组蛋白脱乙酰酶 HDAC1、HDAC2、HDAC3、HDAC6、HDAC8 和 HDAC10 是还原形式的硫辛酸和硫辛酰胺的分子靶标。重要的是，只有天然存在的 ( R )-对映体才能在生理相关浓度下抑制 HDAC，并导致 HDAC 底物过度乙酰化。( R )-硫辛酸和硫辛酰胺对 HDAC 的抑制作用解释了为什么这两种化合物都能防止细胞中应激颗粒的形成，并且还可能为硫辛酸引起的许多其他表型效应提供分子原理。