Malate dehydrogenase 1 and 2 (MDH1/2)

Malate dehydrogenase 1 (MDH1) and malate dehydrogenase 2 (MDH2) are essential metabolic enzymes that catalyze the reversible conversion of malate to oxaloacetate using the NAD+/NADH cofactor system [3, 14]. MDH1 is primarily located in the cytosol, where it participates in the malate-aspartate shuttle and helps maintain the NAD+ pool required for glycolysis, while MDH2 is a key enzyme in the mitochondrial tricarboxylic acid (TCA) cycle [3, 5]. In various cancers, such as non-small cell lung cancer and colorectal cancer, these enzymes are often overexpressed to facilitate metabolic reprogramming, supporting rapid growth and survival under hypoxic conditions [1, 16, 17]. The dual targeting of MDH1 and MDH2 (often denoted as MDH1 x MDH2) is an emerging therapeutic strategy aimed at simultaneously disrupting mitochondrial energy production and cytosolic redox homeostasis [1, 18]. Small molecule dual inhibitors, such as LW1497, have shown the ability to reduce intracellular ATP levels and suppress the accumulation of hypoxia-inducible factor-1 alpha (HIF-1α), leading to potent antitumor effects in preclinical models [1, 9, 16]. Despite their potential, the fundamental role of MDH in normal cellular metabolism necessitates careful evaluation of the therapeutic window to minimize toxicity to healthy tissues [2, 3].

Other names

MDH1 x MDH2MDH1/2MDH1/MDH2Cytosolic malate dehydrogenase and mitochondrial malate dehydrogenase

Dual inhibition of cytosolic (MDH1) and mitochondrial (MDH2) malate dehydrogenases, which disrupts the malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle, leading to impaired cellular respiration, reduced ATP production, and suppression of HIF-1α-mediated signaling.