Huang Shuai, Shi Hang, Shi Zhidan, Wu Jiawei, He Ling
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Biogerontology. 2025 Apr 25;26(3):97. doi: 10.1007/s10522-025-10236-9.
Vorinostat, a pan histone deacetylases (HDACs) inhibitor clinically approved for cutaneous T-cell lymphoma, exerts therapeutic effects by inducing tumor cell death and cycle arrest. Intriguingly, a previously unrecognized hormetic role of low-dose vorinostat in Caenorhabditis elegans. Subtoxic concentrations of vorinostat (1 μM) significantly extended lifespan, enhanced healthspan, and improved resistance to oxidative and heat stress, while ameliorating Aβ-induced paralysis. qPCR analysis demonstrated dose-dependent bidirectional regulation of stress-resistance genes (sod-3, hsp-16.2, skn-1, gst-4, act-1), with low doses of vorinostat upregulating these genes whereas higher doses (10 μM) exerted suppressive or neutral effects. Mechanistically, vorinostat-induced hormesis required functional SKN-1 signaling, as evidenced by its capacity to activate skn-1 and downstream targets (hsp-16.2, gst-4, act-1). Crucially, RNAi-mediated skn-1 knockdown completely abolished the pro-longevity and stress-resistant phenotypes. These findings establish vorinostat as a novel hormetin that enhances organismal resilience through SKN-1 pathway activation, providing new insights into HDAC inhibitor biology and aging intervention strategies.
伏立诺他是一种临床上已被批准用于治疗皮肤T细胞淋巴瘤的泛组蛋白去乙酰化酶（HDACs）抑制剂，它通过诱导肿瘤细胞死亡和细胞周期停滞发挥治疗作用。有趣的是，低剂量伏立诺他在秀丽隐杆线虫中具有一种先前未被认识到的兴奋效应作用。亚毒性浓度的伏立诺他（1 μM）显著延长了线虫寿命，增强了健康寿命，并提高了对氧化应激和热应激的抵抗力，同时改善了Aβ诱导的麻痹。qPCR分析表明，应激抗性基因（sod-3、hsp-16.2、skn-1、gst-4、act-1）存在剂量依赖性双向调节，低剂量伏立诺他上调这些基因，而高剂量（10 μM）则发挥抑制或中性作用。从机制上讲，伏立诺他诱导的兴奋效应需要功能性的SKN-1信号传导，这可通过其激活skn-1及其下游靶点（hsp-16.2、gst-4、act-1）的能力得到证明。至关重要的是，RNA干扰介导的skn-1基因敲低完全消除了延长寿命和抗应激的表型。这些发现确立了伏立诺他作为一种新型的兴奋效应剂，它通过激活SKN-1途径增强机体的适应能力，为HDAC抑制剂生物学和衰老干预策略提供了新的见解。
