ALDH2 functions as an independent favorable prognostic biomarker and suppresses multiple myeloma progression through regulation of the E2F signaling pathway

Abstract Background Multiple Myeloma (MM) remains an incurable plasma cell malignancy characterized by frequent relapse and therapeutic resistance. Identification of microenvironment-related prognostic biomarkers and mechanistic drivers is urgently needed. This study aimed to investigate the clinical significance and functional role of ALDH2 in MM and to elucidate its regulatory mechanism in tumor progression. Methods Single-cell RNA sequencing data (GSE271107) identified differentially expressed genes in plasmacytoid dendritic cells (pDCs) between MM patients and healthy donors. Integrated bioinformatics approaches, including PPI network construction and LASSO-Cox regression, screened prognostic hub genes, with independent validation in multiple cohorts (GSE4581, GSE24080, GSE82307). Immune infiltration, GSEA, and correlation analyses explored functional pathways. Serum ALDH2 levels were measured by ELISA in 47 MM patients and 80 controls. In vitro gain- and loss-of-function experiments in U266 and LAMA-84 cell lines assessed proliferation and apoptosis. Results ALDH2 was identified as a key prognostic hub gene derived from pDC-related differential expression analysis. High ALDH2 expression was significantly associated with prolonged overall survival and superior therapeutic response across independent datasets. Multivariate Cox regression confirmed ALDH2 as an independent favorable prognostic factor. Immune infiltration analysis revealed a negative correlation between ALDH2 expression and malignant plasma cell abundance. GSEA demonstrated that ALDH2 high-expression samples were significantly negatively enriched in the E2F signaling pathway. ALDH2 expression was negatively correlated with CCND2, CDK4, CDK6, and E2F1, and positively correlated with RB1, suggesting inhibition of cell cycle progression. Clinically, serum ALDH2 levels were significantly reduced in MM patients compared to healthy controls and were markedly lower in poor responders (AUC = 0.89 for response prediction). Functionally, ALDH2 overexpression suppressed proliferation, promoted apoptosis, downregulated PCNA, and upregulated CDKN1A and CDKN2A in MM cells. Conclusions ALDH2 acts as a tumor suppressor and an independent favorable prognostic biomarker in MM. Its high expression inhibits MM cell proliferation and promotes apoptosis through suppression of the E2F signaling axis. Circulating ALDH2 levels may serve as a minimally invasive biomarker for disease stratification and therapeutic response prediction. These findings provide mechanistic insight into microenvironment-associated metabolic regulation in MM and highlight ALDH2 as a potential therapeutic target.