Strategies that regulate LSD1 for novel therapeutics

Histone methylation plays a crucial role in regulating chromatin structure and gene transcription, which is essential for epigenetic modifications. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is universally overexpressed in various diseases, making it a promising therapeutic target. Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage. LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9 (H3K4/H3K9), resulting in either transcription repression or activation. While the roles of LSD1 in transcriptional regulation are well-established, studies have revealed that LSD1 can also be dynamically regulated by other factors. For example, the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1. Moreover, some post-transcriptional modifications and cellular metabolites can also regulate LSD1 expression and its demethylase activity. Therefore, in this review, we summarize how proteins involved in the transcriptional corepressor complex formation, post-translational modification, and metabolites act as regulatory factors for LSD1 activity through direct interaction or other mechanisms.