Abstract
The Jumonji C domain-containing (JMJD) family of histone demethylases constitutes an essential class of epigenetic regulators that dynamically sculpt gene expression programs through the erasure of methyl groups from histone lysine and arginine residues. Dysregulation of these enzymes is increasingly implicated in the pathogenesis of a wide spectrum of human diseases. Yet, a fragmented, disease-specific understanding has thus far hindered a unified view of their functions across different pathological states. In this review, we provide a comprehensive and comparative analysis of the JMJD family, synthesizing their roles and mechanisms across diverse human conditions, including cancer, neurological disorders, inflammatory, autoimmune, cardiovascular, and metabolic diseases. We highlight that individual JMJD proteins can function paradoxically as both promoters and suppressors of pathology, a duality determined by the specific cellular and pathological context. A key novelty of our work is its integrated, cross-disease perspective, which moves beyond conventional silos to illuminate common pathophysiological pathways and unique regulatory networks orchestrated by these epigenetic erasers. Furthermore, we critically assess the associated therapeutic landscape, summarizing advances in the development of small-molecule JMJD inhibitors and discussing innovative strategies to tackle enduring challenges, such as enzymatic redundancy and selectivity. By integrating insights from disparate disease models, this review seeks to forge a holistic understanding of JMJD biology and accelerate the development of novel epigenetic therapeutics directed at this pivotal protein family.