Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by increased platelet destruction and insufficient platelet production. Recent research has highlighted the central role of epigenetic regulation, particularly DNA methylation, in the pathogenesis of ITP. Concurrently, vitamin D deficiency has been confirmed to be associated with the occurrence, development, and treatment response of ITP. This review systematically elaborates on the abnormalities in DNA methylation in ITP (e.g., downregulation of DNMT3A/3B expression, S-adenosylhomocysteine (SAH) accumulation leading to hypomethylation) and their impact on T/B cell dysfunction, Treg/Th17 imbalance, and impaired megakaryocyte maturation. It delves into the mechanisms by which vitamin D directly or indirectly (e.g., by regulating DNMTs, miRNAs, histone modifications) modulates DNA methylation status through the vitamin D receptor (VDR) signaling pathway. The latest clinical evidence for drugs targeting DNA methylation (e.g., low-dose decitabine) and vitamin D supplementation therapy is critically reviewed, with a specific focus on analyzing the synergistic potential of their combined application. Based on recent studies, the theoretical framework of the “Vitamin D-DNA Methylation Axis” as a novel target for ITP diagnosis and treatment is proposed, providing a basis for developing personalized epigenetic therapeutic strategies.
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