Etfa, an electron transfer flavoprotein, is involved in multiple biological processes. In fatty acid, amino acid, and choline metabolism, it plays a crucial role as mutations in its promoter can lead to multiple acyl-CoA dehydrogenase deficiency (MADD), an autosomal recessive disorder [1]. It is also associated with other pathways, such as being among the enzymes with lysine crotonylation regulated by Acox2 in hepatic metabolic homeostasis [2]. Additionally, in colorectal cancer, its expression is regulated by NBPF4 and EZH2, influencing cancer progression [3].

In a study, a novel homozygous promoter variant in ETFA (c.-85G > A) was identified in a MADD patient with normal clinical molecular sequencing of related genes. This variant led to decreased ETFA protein expression in lymphoblasts and reduced promoter activity, suggesting a late-onset form of MADD (Type III) [1]. In Clostridium perfringens, inactivation of etfA blocked late-stage sporulation and reduced dipicolinic acid (DPA) levels, as EtfA catalyzes the formation of DPA [4]. In Holstein-Friesian bulls, the ETFA genotype was associated with the activity of antioxidant enzymes in cryopreserved sperm, with the TT genotype having the highest glutathione peroxidase activity [5]. In the context of hypertension with atherosclerosis, platelet microparticle-derived miR-320b inhibits disease development by targeting ETFA [6]. Also, a genetic variant in ETFA (rs1801591) was associated with increased risk of non-glioblastoma glioma in Han Chinese individuals [7].

In summary, Etfa is essential in various metabolic pathways and has implications in multiple disease conditions. Studies using genetic models and patient-based research have revealed its role in MADD, sporulation in bacteria, antioxidant enzyme regulation in sperm, and in diseases like hypertension with atherosclerosis and glioma, enhancing our understanding of its biological functions and disease-related mechanisms.