HADHB, encoding the beta-subunit of 3-hydroxy acyl-CoA dehydrogenase, is closely related to energy metabolism, especially fatty acid beta-oxidation (FAO). It forms a heterodimer with HADHA and functions as an FAO enzyme [2]. This process is crucial for long-chain fatty acid oxidation, and its associated pathways impact overall energy homeostasis in cells [1].

Mutations in the HADHB gene lead to Mitochondrial Trifunctional Protein (MTP) deficiency, a rare autosomal recessive disorder [1]. Patients with MTP deficiency cannot metabolize long-chain fatty-acids, resulting in various symptoms like early-onset cardiomyopathy, recurrent hypoketotic hypoglycemia, sensorimotor neuropathy, and episodic rhabdomyolysis [1].

In malignant lymphoma, HADHB is frequently overexpressed in high-grade lymphoma subtypes and is an independent predictor of poor prognosis, with its knockdown suppressing cell proliferation [2]. In colorectal cancer, chronic cadmium exposure reduces HADHB expression via TET2-mediated hypermethylation of its promoter, contributing to cancer progression [3]. In clear cell renal cell carcinoma (ccRCC), downregulation of HADHB inhibits mitochondrial FAO, leading to lipid accumulation, reduced ATP production, and increased invasive potential [4].

In Drosophila, neuron-specific knockdown of the HADHB homologue (dHADHB) shortens lifespan, reduces locomotor and learning abilities, and causes abnormal synapse morphology [5]. In humans, HADHB mutations can cause infantile-onset axonal Charcot-Marie-Tooth disease [6]. The HADHB gene also modulates the proliferation and differentiation of bovine preadipocytes by regulating key genes [7].

In conclusion, HADHB plays a vital role in fatty acid beta-oxidation and energy metabolism. Studies, including those using gene-knockdown models in Drosophila and functional studies in human diseases, have revealed its significance in various pathological conditions such as MTP deficiency, different cancers, and neurodegenerative-like disorders. Understanding HADHB's function provides insights into the underlying mechanisms of these diseases and potential therapeutic targets.