Aldehyde dehydrogenase family 3 member A2 (ALDH3A2)

Aldehyde dehydrogenase family 3 member A2 (ALDH3A2), also known as fatty aldehyde dehydrogenase (FALDH), is a critical enzyme involved in the oxidation of long-chain aliphatic aldehydes into fatty acids [1, 2]. This NAD+-dependent enzyme is primarily localized in the endoplasmic reticulum and peroxisomes, where it plays a vital role in lipid metabolism, including the degradation of sphingosine 1-phosphate and the detoxification of reactive aldehydes generated by lipid peroxidation [6, 8]. Mutations in the ALDH3A2 gene are the primary cause of Sjögren-Larsson syndrome (SLS), a rare autosomal recessive neurocutaneous disorder characterized by ichthyosis, spasticity, and intellectual disability [2, 5]. In SLS, the loss of enzyme activity leads to the toxic accumulation of fatty aldehydes and alcohols, which disrupt the structure and function of protective membranes in the skin and nervous system [4, 9]. In the context of oncology, ALDH3A2 has emerged as a potential therapeutic target and prognostic biomarker; for instance, its inhibition has been shown to induce ferroptosis-like cell death in acute myeloid leukemia (AML) cells [11, 29]. While specific clinical inhibitors for ALDH3A2 are still under investigation, certain drugs like bezafibrate have been shown to stimulate its expression via PPAR-alpha activation, and selective activators like Alda-89 are being explored to restore function in SLS patients [24]. Additionally, general aldehyde dehydrogenase inhibitors like disulfiram can irreversibly inactivate the enzyme, although they lack specificity [21, 31]. Overall, ALDH3A2 is essential for maintaining cellular redox balance and proper lipid homeostasis, making it a target of interest for both metabolic and malignant diseases [8, 11].

Other names

Fatty aldehyde dehydrogenaseFALDHAldehyde dehydrogenase 10ALDH10Microsomal aldehyde dehydrogenase

Induction of gene expression via PPAR-alpha activation; Irreversible enzyme inhibition via covalent modification; Selective enzyme activation via chemical chaperoning.