目前正在从周围神经病到癌症的临床试验中探索抑制 HDAC6 的酶功能。选择性 HDAC6 抑制剂的发现进展使得研究用于治疗 PNS 和 CNS 适应症的高效脑渗透性和外周限制性化合物成为可能。这篇综述探讨了 HDAC6 在细胞中的多因素作用、PNS 和 CNS 疾病的常见病理特征，以及 HDAC6 如何调节这些机制。分析了 HDAC6 的药理学抑制和基因敲除/敲除研究作为 PNS 和 CNS 适应症的治疗策略。此外，我们还描述了 HDAC6 PET 示踪剂的最新进展及其在 CNS 适应症中的应用。最后，我们探讨了 HDAC6 抑制剂化合物（例如异羟肟酸、氟甲基恶二唑、HDAC6 降解剂和硫醇基抑制剂）的进展和挑战。基于广泛的临床前证据，HDAC6 的药理学抑制是治疗 PNS 和 CNS 的有前途的方法鉴于其参与神经退行性变和衰老相关的细胞过程。尽管选择性 HDAC6 抑制剂的开发取得了进展，但在 PNS 和 CNS 适应症中长期给药的安全性问题仍然存在，而抑制 HDAC6 功能的新型化合物类别和模式的开发提供了一种减轻其中一些安全性问题的方法。

Inhibition of the enzymatic function of HDAC6 is currently being explored in clinical trials ranging from peripheral neuropathies to cancers. Advances in selective HDAC6 inhibitor discovery allowed studying highly efficacious brain penetrant and peripheral restrictive compounds for treating PNS and CNS indications.This review explores the multifactorial role of HDAC6 in cells, the common pathological hallmarks of PNS and CNS disorders, and how HDAC6 modulates these mechanisms. Pharmacological inhibition of HDAC6 and genetic knockout/knockdown studies as a therapeutic strategy in PNS and CNS indications were analyzed. Furthermore, we describe the recent developments in HDAC6 PET tracers and their utility in CNS indications. Finally, we explore the advancements and challenges with HDAC6 inhibitor compounds, such as hydroxamic acid, fluoromethyl oxadiazoles, HDAC6 degraders, and thiol-based inhibitors.Based on extensive preclinical evidence, pharmacological inhibition of HDAC6 is a promising approach for treating both PNS and CNS disorders, given its involvement in neurodegeneration and aging-related cellular processes. Despite the progress in the development of selective HDAC6 inhibitors, safety concerns remain regarding their chronic administration in PNS and CNS indications, and the development of novel compound classes and modalities inhibiting HDAC6 function offer a way to mitigate some of these safety concerns.