Roles of KDM5 demethylases in therapeutic resistance of cancers.

Epigenetic modifications, including the regulation of histone H3 lysine 4 methylation (H3K4me2/3), play critical roles in maintaining normal tissue homeostasis and influencing the progression of cancer, including growth, invasion, metastasis, and therapeutic resistance. The demethylation of H3K4me2/3 is orchestrated by the KDM5 demethylase family, comprising KDM5A, KDM5B, KDM5C, and KDM5D. Recent studies have highlighted the pivotal role of KDM5 demethylases in mediating resistance to cancer therapies, encompassing chemoresistance, radioresistance, immune evasion, and targeted therapy resistance. This review provides a comprehensive overview of the regulatory mechanisms by which KDM5 demethylases contribute to these resistance pathways, with a focus on their molecular targets and interactions within the tumor microenvironment. Furthermore, we discuss emerging therapeutic strategies aimed at overcoming treatment resistance by targeting KDM5 demethylases. These insights provide a foundation for the development of innovative therapeutic interventions to enhance the efficacy of existing cancer treatments, offering a transformative approach to improving long-term patient survival and quality of life.