HADHA, also known as hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha, is a key enzyme in mitochondrial β-oxidation. It is involved in fatty acid oxidation (FAO) and plays a role in regulating energy metabolism-related pathways. Its function is crucial for maintaining normal physiological activities in cells and organisms [2,6].

In mice, liver-specific HADHA overexpression reversed hepatic gluconeogenesis, while HADHA knockdown augmented glucagon response, indicating its role in restraining hepatic glucagon response through promoting β-hydroxybutyrate production, which may be promising for treating diabetes [1]. HADHA-Knockdown cells and mouse embryonic fibroblasts (MEFs) derived from HADHA-Knockout mice displayed reduced supercomplexes (SCs) assembly and defective oxidative phosphorylation (OXPHOS), suggesting that HADHA participates in SCs assembly and couples FAO and OXPHOS [2]. In glioma, knocking down HADHA led to decreased proliferation, enhanced apoptosis, and inhibited migration of glioma cells, as HADHA accelerates MDM2-mediated p53 ubiquitination [3]. In ovarian cancer, HADHA overexpression was observed, and its suppression hindered cell growth and migration while promoting apoptosis, with CDK1 identified as its target [4]. In non-alcoholic fatty liver disease (NAFLD), knockdown of HADHA in cells and overexpression in mice demonstrated its role in alleviating hepatic steatosis and oxidative stress by inactivating the MKK3/MAPK pathway [5].

In conclusion, HADHA is essential for energy metabolism-related processes such as mitochondrial β-oxidation, FAO, and OXPHOS. Studies using HADHA knockout or knockdown models have revealed its significant roles in diseases including diabetes, glioma, ovarian cancer, and NAFLD, providing potential therapeutic targets for these conditions.