Histone lysine demethylases in the third decade: biology and therapeutic prospects.

Histone lysine demethylases (KDMs), discovered with LSD1 (KDM1A) over two decades ago, have emerged as key regulators of chromatin and gene expression, with clinical LSD1 inhibitors advancing.

• Why it matters: Their context-dependent roles as oncogenes or tumour suppressors complicate therapeutic targeting, and gaps remain in understanding biology, substrate specificity, and interaction networks.
• What they did: This Review synthesizes KDM functions across metabolic and immune regulation and cancer, and surveys the inhibitor landscape, focusing on LSD1 inhibitors in clinical trials.
• The result: Advancing KDM therapeutics will require more potent and selective inhibitors, biomarkers of response, improved combinatorial strategies, and innovative drug discovery approaches.

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