Mitochondria-associated programmed cell death: elucidating prognostic biomarkers, immune checkpoints, and therapeutic avenues in multiple myeloma

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation of plasma cells. Mitochondrial dysfunction and dysregulated programmed cell death (PCD) pathways have been implicated in MM pathogenesis. However, the precise roles of mitochondria-related genes (MRGs) and PCD-related genes (PCDRGs) in MM prognosis remain unclear. Methods: Transcriptomic data from MM patients and healthy controls were analyzed to identify differentially expressed genes (DEGs). Candidate genes were selected by intersecting DEGs with curated lists of MRGs and PCDRGs. Univariate Cox, least absolute shrinkage and selection operator (LASSO), multivariate Cox, and stepwise regression analyses identified prognostic genes among the candidates. A risk model was constructed from these genes, and patients were stratified into high- and low-risk groups for survival analysis. Independent prognostic factors were incorporated into a nomogram to predict MM patient outcomes. Model performance was evaluated using calibration curves, receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA). Finally, associations between prognostic genes and immune cell infiltration/drug responses were explored. Results: 2,192 DEGs were detected between MM and control samples. 30 candidate genes were identified at the intersection of DEGs, 1,136 MRGs, and 1,548 PCDRGs. TRIAP1, TOMM7, PINK1, CHCHD10, PPIF, BCL2L1, and NDUFA13 were selected as prognostic genes. The risk model stratified patients into high- and low-risk groups with significantly different survival probabilities. Age, gender, ISS stage, and risk score were independent prognostic factors. The nomogram displayed good calibration and discriminative ability (AUC) in predicting survival, with clinical utility demonstrated by DCA. 9 immune cell types showed differential infiltration between MM and controls, with significant associations to risk scores and specific prognostic genes. 57 drugs, including nelarabine and vorinostat, were predicted to interact with the prognostic genes. Ultimately, qPCR in clinical samples from MM patients and healthy donors validated the expression levels of the seven key prognostic genes, corroborating the bioinformatic findings. Conclusion: Seven genes (TRIAP1, TOMM7, PINK1, CHCHD10, PPIF, BCL2L1, NDUFA13) involved in mitochondrial function and PCD pathways were identified as prognostic markers in MM. These findings provide insights into MM biology and prognosis, highlighting potential therapeutic targets.