The NSDHL/c-Myc/PKM2 Axis Drives Glycolytic Reprogramming and Tumor Growth in Multiple Myeloma.

Multiple myeloma (MM) remains largely incurable because of its complex biology and frequent disease relapse. Metabolic reprogramming is increasingly recognized as a critical contributor to MM progression. NAD (P)-dependent steroid dehydrogenase-like protein (NSDHL) has been highlighted as an unfavorable metabolism-related prognostic gene in plasma cell myeloma, but its functional significance and metabolic role in MM remain unclear. Publicly available MM transcriptomic datasets and the MMRF-CoMMpass cohort were analyzed to evaluate NSDHL expression and its clinical relevance. Cell proliferation was assessed using CCK-8 assays, while glucose consumption, lactate production, and extracellular acidification rate were measured to evaluate glycolytic activity. RNA sequencing was performed following NSDHL knockdown. NSDHL was upregulated in MM and associated with advanced disease stage and poor overall survival. NSDHL knockdown suppressed MM cell proliferation and glycolytic activity. Mechanistically, NSDHL reduced c-Myc phosphorylation at T58 while promoting phosphorylation at S62, thereby inhibiting proteasome-dependent degradation of c-Myc and stabilizing the protein. Stabilized c-Myc subsequently enhanced the transcriptional expression of Pyruvate kinase M2 (PKM2), leading to increased glycolysis. Our data reveal a novel NSDHL/c-Myc/PKM2 regulatory axis that drives glycolytic reprogramming and MM cell proliferation, highlighting NSDHL as a potential prognostic biomarker and therapeutic target in MM.