MDH1B (malate dehydrogenase 1B) is a metabolic enzyme with NAD+-dependent L-malate dehydrogenase activity that participates in the tricarboxylic acid cycle and malate metabolism 1. Unlike the widely expressed MDH1 and MDH2 isoforms, MDH1B is expressed only in a limited subset of tissues 1. The gene functions within a regulatory axis where CREB1 transcriptionally controls MDH1B expression; ox-LDL-induced suppression of CREB1 downregulates MDH1B, impairing malate production and subsequently disrupting mitochondrial membrane potential and ATP generation in endothelial cells 2. MDH1B overexpression restores malate levels and mitigates endothelial dysfunction, establishing the CREB1-MDH1B-malate axis as a bridge between transcriptional regulation and metabolic homeostasis 2. Clinically, reduced MDH1B expression correlates with altered TCA cycle flux in skeletal muscle of rheumatoid arthritis patients, with baseline downregulation associated with greater disease activity improvements following high-intensity interval training 3. MDH1B has been identified as a candidate susceptibility gene for erectile dysfunction through transcriptome-wide association analysis 4. However, specific mutations in MDH1B and their pathogenic mechanisms remain poorly characterized compared to other MDH isoforms 1.