BackgroundMultiple myeloma (MM) is a plasma cell malignancy prone to drug resistance, with unclear autophagy/apoptosis interactions in its etiology. This study explored transcription factor E4BP4''s role in MM autophagy and apoptosis.MethodsTranscriptomic data from GEO and TCGA assessed E4BP4 expression and clinicopathological correlations. E4BP4 expression in MM cell line U266 and normal PBMCs was analyzed via western blotting, RT-qPCR, and immunohistochemistry. Autophagy/apoptosis markers were measured using CCK-8, flow cytometry, electron microscopy, and immunofluorescence. Molecular docking identified E4BP4 DNA-binding sites. Co-immunoprecipitation, luciferase reporter assays, and ChIP-qPCR analyzed E4BP4 transcriptional activity. E4BP4 knockdown effects were tested in mouse xenografts.ResultsE4BP4 was overexpressed in MM tumor tissues versus non-cancerous tissues, and in U266 cells versus PBMCs. High E4BP4 suppressed apoptosis and autophagy in MM cells. E4BP4 overexpression upregulated HDAC3 transcription, activated mTOR signaling, and reduced H3K9Ac/H3K27Ac association with Beclin1 promoter, decreasing Beclin1 expression. E4BP4 overexpression reduced U266 sensitivity to dexamethasone, while knockdown enhanced drug sensitivity. E4BP4 knockdown inhibited U266 xenograft growth in mice, with combined knockdown and dexamethasone yielding additive effects.ConclusionE4BP4 promotes MM progression by upregulating HDAC3, reducing histone acetylation and Beclin1 transcription to suppress autophagy/apoptosis. Its role in dexamethasone resistance highlights E4BP4 as a potential therapeutic target.