HADHB, encoding the beta-subunit of 3-hydroxy acyl-CoA dehydrogenase, is closely related to energy metabolism, especially in fatty acid beta-oxidation (FAO) pathway [2,3,4,7]. It forms a heterodimer with HADHA and functions as an FAO enzyme [2]. HADHB is also involved in adipocyte regulation, influencing preadipocyte proliferation and differentiation by modulating key genes [7].

Mutations in the HADHB gene lead to Mitochondrial Trifunctional Protein (MTP) deficiency, a rare autosomal recessive disorder affecting long-chain fatty acid oxidation [1]. Patients with MTP deficiency suffer from various symptoms such as early-onset cardiomyopathy, recurrent hypoketotic hypoglycemia, sensorimotor neuropathy, and episodic rhabdomyolysis [1]. In malignant lymphoma, HADHB overexpression is frequent in high-grade lymphoma subtypes and is an independent predictor of poor prognosis. In vitro analysis shows that HADHB knockdown suppresses 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 promotes lipid accumulation, inhibits mitochondrial fatty acid β-oxidation, and enhances the invasive potential of cancer cells [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].

In conclusion, HADHB plays a crucial role in fatty acid metabolism, adipocyte regulation, and is associated with multiple diseases including mitochondrial disorders, malignant lymphoma, colorectal cancer, ccRCC, and certain neuropathies. Studies using genetic models like Drosophila knockdown and patient-based genetic analysis have provided insights into its functions and disease associations.

References:

1. Dagher, Robin, Massie, Rami, Gentil, Benoit J. 2021. MTP deficiency caused by HADHB mutations: Pathophysiology and clinical manifestations. In Molecular genetics and metabolism, 133, 1-7. doi:10.1016/j.ymgme.2021.03.010. https://pubmed.ncbi.nlm.nih.gov/33744096/

2. Sekine, Yuji, Yamamoto, Kouhei, Kurata, Morito, Yamamoto, Masahide, Kitagawa, Masanobu. 2021. HADHB, a fatty acid beta-oxidation enzyme, is a potential prognostic predictor in malignant lymphoma. In Pathology, 54, 286-293. doi:10.1016/j.pathol.2021.06.119. https://pubmed.ncbi.nlm.nih.gov/34531036/

3. Li, Lingling, Jiang, Min, Wang, Weimin, Huang, Yefei, Chen, Yansu. 2024. DNA demethylase TET2-mediated reduction of HADHB expression contributes to cadmium-induced malignant progression of colorectal cancer. In Ecotoxicology and environmental safety, 280, 116579. doi:10.1016/j.ecoenv.2024.116579. https://pubmed.ncbi.nlm.nih.gov/38865940/

4. Li, Xin, Wu, Mengmeng, Chen, Guijuan, Gan, Weidong, Li, Dongmei. 2025. The Role of HADHB in Mitochondrial Fatty Acid Metabolism During Initiation of Metastasis in ccRCC. In Molecular carcinogenesis, 64, 923-935. doi:10.1002/mc.23898. https://pubmed.ncbi.nlm.nih.gov/39991877/

5. Li, Jialin, Suda, Kojiro, Ueoka, Ibuki, Takashima, Hiroshi, Yamaguchi, Masamitsu. 2019. Neuron-specific knockdown of Drosophila HADHB induces a shortened lifespan, deficient locomotive ability, abnormal motor neuron terminal morphology and learning disability. In Experimental cell research, 379, 150-158. doi:10.1016/j.yexcr.2019.03.040. https://pubmed.ncbi.nlm.nih.gov/30953623/

6. Lu, Yuanyuan, Wu, Rui, Meng, Lingchao, Yuan, Yun, Wang, Zhaoxia. . HADHB mutations cause infantile-onset axonal Charcot-Marie-Tooth disease: A report of two cases. In Clinical neuropathology, 37, 232-238. doi:10.5414/NP301097. https://pubmed.ncbi.nlm.nih.gov/29956646/

7. Yang, Chaoyun, Wang, Shuzhe, Qi, Yunxia, Guan, Ran, Huang, Zengwen. 2025. Mechanisms of adipocyte regulation: Insights from HADHB gene modulation. In PloS one, 20, e0319384. doi:10.1371/journal.pone.0319384. https://pubmed.ncbi.nlm.nih.gov/40146690/