Introduction: X-linked MAGT1 deficiency (XMEN) is a rare primary immunodeficiency causing impaired NKG2D expression and defective cytotoxicity . There is currently no effective targeted therapy . TUSC3, a paralog of MAGT1, is epigenetically silenced in immune and liver tissues, preventing its compensatory upregulation. Objectives: To validate clinical and immunological features of XMEN in a pediatric cohort and propose a therapeutic strategy via TUSC3 epigenetic activation. Methods: Retrospective analysis of 18 pediatric patients with MAGT1 variants. Clinical data, immunoglobulins, lymphocyte subsets, and liver enzymes were documented. NKG2D expression and cytotoxicity were assessed. In vitro effects of Decitabine and Panobinostat on TUSC3 expression and function were evaluated. Results: All patients showed decreased NKG2D expression. EBV infection (72%) and lymphoma (28%) were prevalent; 56% had elevated liver enzymes. Most harboured early termination variants. Cytotoxicity was significantly impaired. Decitabine and Panobinostat synergistically upregulated TUSC3 expression, restored NKG2D surface expression, enhanced cytotoxicity , and ameliorated liver enzyme release. Conclusions: This study delineates XMEN's clinical and immunological spectrum in a Chinese pediatric cohort. Deficient NKG2D expression and impaired cellular cytotoxicity represent core immunological defects in XMEN. Epigenetic silencing of TUSC3 is a key mechanism. Combining Decitabine and Panobinostat is a promising targeted strategy to improve immune deficiency and liver abnormalities in XMEN.