Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
Front Immunol. 2023 Jul 21;14:1168848. doi: 10.3389/fimmu.2023.1168848. eCollection 2023.
Histone deacetylase 6 (HDAC6), an almost exclusively cytoplasmic enzyme, plays an essential role in many biological processes and exerts its deacetylation-dependent/independent effects on a variety of target molecules, which has contributed to the flourishing growth of relatively isoform-specific enzyme inhibitors. Renal transplantation (RT) is one of the alternatively preferred treatments and the most cost-effective treatment approaches for the great majority of patients with end-stage renal disease (ESRD). HDAC6 expression and activity have recently been shown to be increased in kidney disease in a number of studies. To date, a substantial amount of validated studies has identified HDAC6 as a pivotal modulator of innate and adaptive immunity, and HDAC6 inhibitors (HDAC6i) are being developed and investigated for use in arrays of immune-related diseases, making HDAC6i a promising therapeutic candidate for the management of a variety of renal diseases. Based on accumulating evidence, HDAC6i markedly open up new avenues for therapeutic intervention to protect against oxidative stress-induced damage, tip the balance in favor of the generation of tolerance-related immune cells, and attenuate fibrosis by inhibiting multiple activations of cell profibrotic signaling pathways. Taken together, we have a point of view that targeting HDAC6 may be a novel approach for the therapeutic strategy of RT-related complications, including consequences of ischemia-reperfusion injury, induction of immune tolerance in transplantation, equilibrium of rejection, and improvement of chronic renal graft interstitial fibrosis after transplantation in patients. Herein, we will elaborate on the unique function of HDAC6, which focuses on therapeutical mechanism of action related to immunological events with a general account of the tantalizing potential to the clinic.
组蛋白去乙酰化酶 6（HDAC6）是一种几乎完全存在于细胞质中的酶，在许多生物学过程中发挥着重要作用，并对各种靶分子发挥去乙酰化依赖/非依赖效应，这促进了相对同工酶特异性酶抑制剂的蓬勃发展。肾移植（RT）是替代治疗方法之一，也是绝大多数终末期肾病（ESRD）患者最具成本效益的治疗方法。最近的一些研究表明，HDAC6 在肾脏疾病中的表达和活性增加。迄今为止，大量经过验证的研究已经确定 HDAC6 是先天和适应性免疫的关键调节剂，HDAC6 抑制剂（HDAC6i）正在开发和研究中，用于多种免疫相关疾病，使 HDAC6i 成为管理各种肾脏疾病的有前途的治疗候选药物。基于不断积累的证据，HDAC6i 为治疗干预提供了新的途径，以防止氧化应激诱导的损伤，有利于产生与耐受相关的免疫细胞，通过抑制细胞成纤维细胞信号通路的多种激活来减轻纤维化。综上所述，我们认为针对 HDAC6 可能是 RT 相关并发症治疗策略的新方法，包括缺血再灌注损伤的后果、移植中免疫耐受的诱导、排斥反应的平衡以及改善移植后慢性肾移植物间质纤维化。在此，我们将详细阐述 HDAC6 的独特功能，重点介绍与免疫事件相关的治疗作用机制，并概述其在临床应用中的诱人潜力。
