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<p>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&#xa0;<i>Caenorhabditis elegans</i>. Subtoxic concentrations of vorinostat (1&#xa0;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 (<i>sod-3</i>,&#xa0;<i>hsp-16.2</i>,&#xa0;<i>skn-1</i>,&#xa0;<i>gst-4</i>,&#xa0;<i>act-1</i>), with low doses of vorinostat upregulating these genes whereas higher doses (10&#xa0;μM) exerted suppressive or neutral effects. Mechanistically, vorinostat-induced hormesis required functional SKN-1 signaling, as evidenced by its capacity to activate&#xa0;<i>skn-1</i>&#xa0;and downstream targets (<i>hsp-16.2</i>,&#xa0;<i>gst-4</i>,&#xa0;<i>act-1</i>). Crucially, RNAi-mediated <i>skn-1</i> 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.</p>

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Vorinostat, a potential hormetin, extends lifespan and enhances stress resistance via the SKN-1 pathway in Caenorhabditis elegans

  • 期刊论文

  • 发表日期：

    2025年4月25日

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  • Shuai Huang,
  • Hang Shi,
  • Zhidan Shi,
  • Jiawei Wu,
  • Ling He

摘要

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.