The pursuit of tissue regeneration has fueled decades of research in regenerative medicine. Among the numerous types of mesenchymal stem cells (MSCs), dental-derived mesenchymal stem cells (DMSCs) have recently emerged as a particularly promising candidate for tissue repair and regeneration. In recent years, evidence has highlighted the pivotal role of mitochondria in directing and orchestrating the differentiation processes of DMSCs. Beyond mitochondrial energy metabolism, the multifaceted functions of mitochondria are governed by the mitochondrial quality control (MQC) system, encompassing biogenesis, autophagy, and dynamics. Notably, mitochondrial energy metabolism not only governs the decision to differentiate but also exerts a substantial influence on the determination of differentiation directions. Furthermore, the MQC system exerts a nuanced impact on the differentiation of DMSCs by finely regulating the quality and mass of mitochondria. The review aims to provide a comprehensive overview of the regulatory mechanisms governing the multi-directional differentiation of DMSCs, mediated by both mitochondrial energy metabolism and the MQC system. We also focus on a new idea based on the analysis of data from many research groups never considered before, namely, DMSC-based regenerative medicine applications.

2-deoxyglucose (2-DG), targeting Hexokinase I (HKI) to inhibit glycolysis in cancer cells, has inspired drug design. Increasing evidence suggests that its phosphorylated form, 2-deoxyglucose-6-phosphate (2-DG-6-P), may inhibit HKI more effectively, highlighting the need to understand the molecular mechanisms behind this effect. Using molecular simulations, we examined interactions between HKI and its substrates—glucose (G) and glucose-6-phosphate (G-6-P)—and inhibitors—2-DG and 2-DG-6-P. G and G-6-P showed stable interactions with HKI, involving residues like ILE 662, SER 588, and PRO 590, while 2-DG had less stable interactions. However, 2-DG-6-P formed the most stable complex, engaging additional residues such as VAL 663 and THR 848, with enhanced binding through hydrophobic and hydrogen bond interactions facilitated by its phosphorylated group. This study reveals the differential effects of 2-DG and 2-DG-6-P on HKI inhibition, highlighting the unique mechanism of 2-DG post-phosphorylation and supporting the development of targeted HKI inhibitors that exploit cancer cell metabolism.