Myelodysplastic neoplasms are inhibited by Brefeldin A through endoplasmic reticulum stress and autophagy.

Myelodysplastic neoplasms (MDS) are a clonal malignant bone marrow disease with high heterogeneity and a high risk of transformation into acute myeloid leukemia (AML). However, the progression of MDS varies significantly, and the available therapeutic drugs are limited. Brefeldin A (BFA), a natural antibiotic, has not been systematically elucidated for its anti-MDS activity and underlying molecular mechanisms. In this study, SKM-1 and MDS-L cell lines and patient primary bone marrow samples were adopted. Multiple experimental approaches, including CCK-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, RT-qPCR, immunofluorescence staining, transcriptome sequencing, and Western blot, were comprehensively utilized to systematically investigate the effects of BFA on MDS cell proliferation, cell cycle, endoplasmic reticulum stress (ERS), and autophagy. The in vivo anti-tumor validation was conducted using mouse xenograft models. The results showed that BFA significantly inhibited the proliferation of MDS cell lines and patient-derived bone marrow mononuclear cells (BMMCs). Mechanistically, BFA activated the inositol-requiring enzyme 1alpha (IRE1α) pathway to trigger ERS, and then ERS initiated autophagy and caused cell cycle arrest at G2/M phase, ultimately exerting its anti-MDS effect. In vivo experiments preliminarily confirmed that BFA could effectively inhibit MDS progression. These results suggest the fundamental mechanisms by which BFA suppresses MDS, providing a theoretical basis for its development as a new therapeutic drug for MDS.