Hadh, encoding 3-hydroxy acyl CoA dehydrogenase, is a key enzyme in fatty acid β-oxidation. Fatty acid β-oxidation is an important form of energy metabolism, and Hadh participates in steps 2, 3 and 4 of this process. Mitochondrial trifunctional protein (MTP) is crucial in fatty acid β-oxidation, and Hadh has two subtypes, Hadha and Hadhb, which are important subunits of MTP [1].

In male mice, Hadh gene knockout using Nuclease technology technology led to spermatocyte meiosis arrest, increased multinucleated giant germ cells and vacuoles in seminiferous tubules, along with acrosomal dysplasia. The knockout mice showed oligoasthenoteratozoospermia features, such as decreased sperm concentration and motility and increased sperm abnormalities. Fatty acids accumulated in the testis, inflammatory factors increased, and apoptosis-related proteins changed. Inhibiting TNF-α alleviated testis injury [2].

In clear cell renal cell carcinoma (ccRCC), bioinformatics analysis showed Hadh expression was decreased in ccRCC tissues, and its low expression predicted poor prognosis. Overexpressing Hadh in ccRCC cells inhibited their malignant behaviors by attenuating GSH synthesis through inhibition of NRF2 nuclear translocation [3].

In gastric cancer, Western blot analysis revealed decreased Hadh expression in stage I/II samples compared to adjacent normal tissue, and further decrease in stage III/IV samples. Knockdown of Hadh promoted gastric cancer cell migration and invasion via activation of the Akt signaling pathway [4].

In conclusion, Hadh is essential for fatty acid β-oxidation. Gene knockout mouse models have revealed its roles in spermatogenesis, with Hadh deficiency causing oligoasthenoteratozoospermia, and in cancer, where its abnormal expression affects tumor development, prognosis, and progression in ccRCC and gastric cancer. These findings contribute to understanding the biological functions of Hadh and its potential as a therapeutic target in related diseases.