SLFN14: An Elusive Regulator of Megakaryocytes and Platelets in Inherited Thrombocytopenia

Inherited thrombocytopenias (ITs) are a heterogeneous group of bleeding disorders characterized by a persistent reduction in circulating platelets (< 150 × 10⁹/L) and variable clinical severity. To date, pathogenic variants in 44 genes have been linked to inherited thrombocytopenia, and defining these underlying genetic causes remains essential for accurate diagnosis, patient management, and the development of targeted therapies. The gene for Schlafen Family Member 14 (SLFN14) is among the more recently discovered genes, and pathogenic variants in SLFN14 cause inherited thrombocytopenia, primarily associated with bleeding tendencies but without evidence for other systemic symptoms. Remarkably, by searching 'SLFN14' in PubMed, only 32 publications have appeared since the first report about this gene in 2010. These studies suggest that SLFN14 may function as an endoribonuclease and also act as an interferon-inducible antiviral effector that restricts viruses post-entry, placing it within the broader Schlafen innate immune RNA-regulation family. With this review, we aim to synthesize current knowledge on SLFN14, highlighting its structural features, expression profile, enzymatic activities, and role in platelet biogenesis, while examining how pathogenic variants disrupt these processes. We also discuss emerging evidence of its antiviral function and broader implications for RNA regulation, providing a framework to guide future research.