It is well-established that Lysine-specific demethylase 1 (LSD1, also known as KDM1A) roles as a lysine demethylase canonically acting on H3K4me1/2 and H3K9me1/2 for regulating gene expression. Though the discovery of non-histone substrates methylated by LSD1 has largely expanded the functions of LSD1 as a typical demethylase, recent groundbreaking studies unveiled its non-catalytic functions as a second life for this demethylase. We and others found that LSD1 is implicated in the interaction with a line of proteins to exhibit additional non-canonical functions in a demethylase-independent manner. Here, we present an integrated overview of these recent literatures charging LSD1 with unforeseen functions to re-evaluate and summarize its non-catalytic biological roles beyond the current understanding of its demethylase activity. Given LSD1 is reported to be ubiquitously overexpressed in a variety of tumors, it has been generally considered as an innovative target for cancer therapy. We anticipate that these non-canonical functions of LSD1 will arouse the consideration that extending the LSD1-based drug discovery to targeting LSD1 protein interactions non-catalytically, not only its demethylase activity, may be a novel strategy for cancer prevention.

众所周知，赖氨酸特异性去甲基化酶 1（LSD1，也称为 KDM1A）作为赖氨酸去甲基化酶，典型地作用于 H3K4me1/2 和 H3K9me1/2 来调节基因表达。尽管 LSD1 甲基化非组蛋白底物的发现在很大程度上扩展了 LSD1 作为典型去甲基化酶的功能，但最近的突破性研究揭示了其作为这种去甲基化酶的第二生命的非催化功能。我们和其他人发现 LSD1 与一系列蛋白质相互作用有关，以不依赖于去甲基化酶的方式表现出额外的非规范功能。在这里，我们对这些最近的文献进行了综合概述，这些文献赋予 LSD1 不可预见的功能，以重新评估和总结其非催化生物学作用，超出了目前对其去甲基酶活性的理解。据报道，LSD1 在多种肿瘤中普遍过度表达，因此它通常被认为是癌症治疗的创新靶点。我们预计 LSD1 的这些非典型功能将引起人们的考虑，将基于 LSD1 的药物发现扩展到非催化地靶向 LSD1 蛋白相互作用，而不仅仅是其去甲基化酶活性，可能是一种预防癌症的新策略。