组蛋白甲基化在调节基因表达、保持基因组完整性和表观遗传学传承中发挥着关键作用。然而，在许多人类疾病中常观察到组蛋白甲基化的异常表现，尤其是癌症。组蛋白甲基转移酶介导的赖氨酸甲基化可以被赖氨酸去甲基化酶(KDM)逆转，将甲基标记从组蛋白赖氨酸残基中去除。目前，药物抗性是癌症治疗的主要障碍。许多癌症的KDM介导的药物耐受性已被发现，通过改变癌细胞的代谢特征、上调癌干细胞和药物耐受基因的比例以及促进上皮-间质转化和转移能力。此外，不同的癌症对KDM呈现出不同的致癌上瘾。KDM的异常激活或过表达可以改变基因表达特征，增强癌细胞的存活和药物抗性。在本评述中，我们描述了KDM的结构特征和功能、不同癌症对KDM的偏好以及由KDM导致的药物抗性机制。然后，我们概述了用于抗击癌症药物抗性的KDM抑制剂，讨论了KDM作为癌症药物抗性治疗靶点的机遇和挑战。 © 2023 Wiley Periodicals LLC.

Histone methylation plays a key function in modulating gene expression, and preserving genome integrity and epigenetic inheritance. However, aberrations of histone methylation are commonly observed in human diseases, especially cancer. Lysine methylation mediated by histone methyltransferases can be reversed by lysine demethylases (KDMs), which remove methyl marks from histone lysine residues. Currently, drug resistance is a main impediment for cancer therapy. KDMs have been found to mediate drug tolerance of many cancers via altering the metabolic profile of cancer cells, upregulating the ratio of cancer stem cells and drug-tolerant genes, and promoting the epithelial-mesenchymal transition and metastatic ability. Moreover, different cancers show distinct oncogenic addictions for KDMs. The abnormal activation or overexpression of KDMs can alter gene expression signatures to enhance cell survival and drug resistance in cancer cells. In this review, we describe the structural features and functions of KDMs, the KDMs preferences of different cancers, and the mechanisms of drug resistance resulting from KDMs. We then survey KDM inhibitors that have been used for combating drug resistance in cancer, and discuss the opportunities and challenges of KDMs as therapeutic targets for cancer drug resistance.© 2023 Wiley Periodicals LLC.