ALDH6A1 encodes methylmalonate semialdehyde dehydrogenase, a mitochondrial enzyme that catalyzes the oxidation of methylmalonate semialdehyde to propionyl-CoA in the valine catabolic pathway 1. The enzyme exhibits NAD-dependent aldehyde dehydrogenase activity essential for branched-chain amino acid metabolism, particularly valine catabolism 2. ALDH6A1 functions as a tumor suppressor in multiple cancers, with downregulation observed in hepatocellular carcinoma, clear cell renal cell carcinoma, gastric cancer, and colon cancer 2345. Mechanistically, ALDH6A1-generated propionyl-CoA inhibits citrate synthase activity, reducing tricarboxylic acid cycle flux and ATP production, thereby suppressing cancer cell proliferation 2. In colon cancer, ALDH6A1 inhibits the RAS/RAF/MEK/ERK signaling pathway 5. Disease relevance includes methylmalonate semialdehyde dehydrogenase deficiency, characterized by 3-hydroxyisobutyric aciduria and developmental delay, caused by mutations such as c.785C>A (S262Y) and c.184C>T (P62S) 1. ALDH6A1 is also decreased in Alzheimer's disease brain tissue and CSF, representing part of a mitochondrial dysfunction signature 6. Additionally, lysine propionylation of ALDH6A1 at Lys113 increases its activity and NADH production, potentially contributing to postoperative atrial fibrillation through oxidative stress mechanisms 7.