Epigenetic priming with valeric acid unlocks multi-stress resistance in plants by targeted histone deacetylase inhibition

Progressive climate change is driving increasingly devastating crop losses through droughts, heatwaves and other adverse weather. Combined with shrinking arable land and spreading plant diseases, this makes it crucial to enable crops to grow efficiently in unfavorable, dynamic environments. Because stressors demand prompt, highly coordinated responses, plant stress adaptations rely heavily on epigenetic regulation. Histone deacetylases (HDAs), particularly class I, were recently shown to repress these responses. As constitutive defense is energetically costly, tools enabling temporal modulation of such mechanisms are highly sought after in crop biotechnology. This study evaluated whether valeric acid (VA), a five-carbon carboxylic acid, can inhibit HDA and activate plant defense responses. Here we show that VA is a potent HDA inhibitor that confers resistance to multiple abiotic and biotic stresses in Arabidopsis, and further validate the abiotic component in maize and tomato. Despite its simple chemical structure, structural and transcriptomic evidence shows that VA acts by selectively inhibiting two major stress-repressing deacetylases, HDA19 and HDA6. By targeting these epigenetic switches, VA activates natural defense and acclimation responses. Time-course transcriptomic analyses further revealed that priming with VA induces transcriptional memory, which, together with VA-induced metabolic rewiring, enables rapid and efficient responses to future stressors. Most importantly, despite activating energetically demanding defenses, VA promotes vegetative growth and increases yield under normal conditions, thereby breaking the growth-defense trade-off. These findings establish VA as the first epigenetic biostimulant of its kind, capable of improving plant performance under both abiotic and biotic stress while simultaneously increasing crop yield. As the epigenetic mechanisms underlying its action are evolutionarily conserved, VA priming emerges as a promising universal strategy to mitigate the climate-driven global crisis of crop losses.