A latent hydrazone switch turns SP2509 into an optical timer of cell fate

Abstract

Epigenetic inhibitors can reprogram cell states, but their activity is usually governed by fixed dose-response relationships rather than by user-defined temporal commands. Here we show that SP2509, an established reversible LSD1/KDM1A inhibitor, contains a latent ortho-hydroxy acylhydrazone switch that converts this known scaffold into an optical timer for chromatin-dependent cell fate. Irradiation at 430 nm enriches a less active cis-associated state under near-physiological conditions, whereas dark relaxation regenerates the more active trans-associated state with a half-life of 6.5 hours. This reversible conformational change reduces recombinant LSD1 inhibition by approximately 7-fold and is transmitted to H3K9me2 accumulation, proliferation, senescence and apoptosis. Reciprocal light-dark switching experiments reveal a reversible window for senescence-associated arrest in MGC-803 cells and tune population-level entry into apoptosis in OCI-AML3 cells. RNA-seq endpoint comparisons further distinguish photostate-associated transcriptional states, with dark trans-SP2509 producing stronger stress-survival and apoptosis-linked programs than cells maintained under cis-SP2509 conditions. These findings establish latent hydrazone photoisomerization as a compact strategy for converting a static epigenetic inhibitor into a kinetic regulator of chromatin-dependent cell-fate transitions.