Chemogenetic Manipulation of H2S with Spatiotemporal Precision

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High Resolution Image Download MS PowerPoint Slide Hydrogen sulfide (H 2 S) is a signaling molecule with a plethora of biological functions, yet precision tools for modulating its intracellular flux remain scarce. Conventional small-molecule donors and enzymatic systems often suffer from off-target reactivity, uncontrolled release kinetics, and redox crosstalk, confounding mechanistic studies. Here, we establish a Salmonella typhimurium d -cysteine desulfhydrase (stDCyD)-derived chemogenetic tool for controlled H 2 S manipulation in living cells. stDCyD catalyzes the α,β-elimination of d -cysteine to selectively yield bioavailable H 2 S. We term this tool H 2 SWITCH. Our approach exhibits pronounced enantioselectivity for d -cysteine, robust catalytic efficiency at physiological temperatures, and temporal tunability through substrate dosing. This chemogenetic tool provides a chemically defined and interference-free method to unravel the physiological and pathological roles of H 2 S with unprecedented precision in complex biological systems.