A leukemia-derived ENL/AF9 chemical probe enhances neuronal stress resilience and ameliorates ALS phenotypes

SUMMARY Chemical perturbation of chromatin reader proteins provides a precise strategy to interrogate epigenetic control of neuronal stress adaptation. ENL and AF9 are YEATS-domain acyl-lysine readers best characterized in leukemia, but their roles in neurons remain unclear. Here, we use the selective YEATS inhibitor SR-0813 to define ENL/AF9 function in neuronal stress responses across Drosophila and human systems. SR-0813 phenocopies genetic ENL/AF9 reduction by extending lifespan and enhancing stress tolerance in vivo , and improves survival of human neurons under multiple stress conditions, with the strongest effects during endoplasmic reticulum stress. Mechanistically, SR-0813 attenuates PERK-ISR signaling and reduces apoptotic commitment without broadly enhancing proteostasis capacity. Notably, its effects are highly context dependent, conferring protection in stress-signaling-driven models but reduced efficacy or detrimental outcomes under chronic aggregation or mitochondrial stress. These findings identify ENL/AF9 as modulators of stress-response dynamics and highlight YEATS-domain inhibition as a context-dependent strategy to reshape neuronal resilience. GRAPHICAL ABSTRACT siRNA or the YEATS-domain inhibitor SR-0813 suppress the acyl-lysine reader ENL/AF9, extending lifespan and increasing H₂O₂ tolerance in Drosophila . In neurons ( Drosophila and SH-SY5Y), ENL/AF9 inhibition lowers PERK–ISR signaling and apoptosis while maintaining proteostasis. Effects are context dependent: protective under UPR/ISR-dominant stress but potentially detrimental under aggregation or mitochondrial stress. Created with BioRender.