• SFXN3 is a novel prognostic biomarker associated with poor survival in AML. • SFXN3 promotes AML cell growth via activation of Wnt/β-catenin signaling. • The REST–SFXN3 axis enhances leukemic progression and modulates decitabine sensitivity. One of the most diverse types of blood cancer is acute myeloid leukemia, or AML, and there remains an urgent need to identify novel molecular targets for its diagnosis and treatment. The present investigation identified Sideroflexin 3 (SFXN3) as a possible prognostic biomarker in AML by integrating transcriptome and survival data from the TCGA and GTEx databases. Clinical correlation analysis revealed a strong association between increased SFXN3 expression and both advanced age and poor overall survival. Stratified survival analyses confirmed the predictive value of the model across multiple clinical subgroups. It has been demonstrated through the implementation of functional assays that SFXN3 exerts a pivotal role in the promotion of AML cell proliferation and the suppression of apoptosis. This function is primarily attributed to the activation of the Wnt/β-Catenin signaling pathway. Mechanistically, the transcription factor REST was identified as a direct upstream regulator of SFXN3, capable of binding to its promoter region and transcriptionally activating it. The present study has identified the REST–SFXN3–Wnt/β-Catenin axis as a critical regulator of AML cell growth and survival. Furthermore, pharmacological experiments revealed that SFXN3 knockdown significantly enhanced AML cell sensitivity to decitabine, suggesting that co-targeting SFXN3 could improve chemotherapeutic efficacy and help overcome drug resistance. This research provides a comprehensive clarification of the role of SFXN3 in AML, its biological function, and its upstream regulation. Furthermore, the present study unveils a novel signaling pathway involving REST-SFXN3-Wnt/β-Catenin, which may serve as a therapeutic target. These results provide a valuable insight into the underlying causes of AML and offer a potential framework for precision therapy approaches.
Wang et al. (Thu,) studied this question.