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

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.