Cancer cells usually prefer glycolysis to support their proliferation. Our previous studies have shown that the long palate, lung, and nasal epithelial cell clone 1 (LPLUNC1) can up-regulate prohibitin 1 (PHB1) expression to inhibit the proliferation of nasopharyngeal carcinoma (NPC) cells. Given that PHB1 is an important regulator of cell energy metabolism, we explored whether and how LPLUNC1 regulated glucose glycolysis in NPC cells. LPLUNC1 or PHB1 over-expression decreased glycolysis and increased oxidative phosphorylation (OXPHOS)-related protein expression in NPC cells, accompanied by enhancing PHB1 and 14-3-3σ expression and promoting phosphorylated PHB1 nuclear translocation. Coimmunoprecipitation indicated that 14-3-3σ directly interacted with phosphorylated PHB1. PHB1 Y259A mutant over-expression abrogated the decreasing glycolysis and increasing OXPHOS-related protein expression induced by LPLUNC1 over-expression in NPC cells. LPLUNC1 over-expression also increased p53, but decreased c-Myc expression in NPC cells, which were crucial for the decrease in glycolysis and increase in OXPHOS-related protein expression induced by LPLUNC1 over-expression. Finally, we found that treatment with all-trans retinoic acid (ATRA) reduced the viability and clonogenicity of NPC cells, decreased glycolysis and increased OXPHOS-related protein xpression by enhancing LPLUNC1 expression in NPC cells. Therefore, the LPLUNC1-PHB1-p53/c-Myc axis decreased glycolysis in NPC cells and ATRA up-regulated LPLUNC1 expression, a promising drug for intervention of NPC.