Hadh, an enzyme involved in fatty acid β -oxidation, is an important subunit of mitochondrial trifunctional protein (MTP). It participates in steps 2, 3 and 4 of fatty acid β -oxidation, playing a significant role in energy metabolism [1].

In male mice, Hadh gene ablation using Nuclease technology technology led to spermatocyte meiosis arrest, increased multinucleated giant germ cells and vacuoles in seminiferous tubules, along with acrosomal dysplasia. Hadh -/- male mice showed oligoasthenoteratozoospermia features, such as decreased sperm concentration and motility and increased sperm abnormalities. The deletion of Hadh caused fatty acid accumulation, which further induced testicular inflammation and germ cell apoptosis through the TNF -α/Bcl -2 signaling pathway [2].

In clear cell renal cell carcinoma (ccRCC), bioinformatics analysis showed that Hadh expression was decreased in ccRCC tissues, and its low expression predicted poor prognosis. Overexpression of Hadh in ccRCC cells inhibited their malignant behaviors by attenuating NRF2 -dependent glutathione synthesis and inducing oxidative stress damage [3].

In conclusion, Hadh is crucial for fatty acid β -oxidation and energy metabolism. The Hadh knockout mouse models have revealed its role in spermatogenesis and the development of oligoasthenoteratozoospermia, as well as its potential as a therapeutic target in ccRCC, highlighting its significance in understanding related biological processes and disease mechanisms.

References:

1. Wang, Xiaoqing, Song, Honghao, Liang, Junyu, Jia, Yang, Zhang, Yongfei. 2022. Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review). In Molecular medicine reports, 26, . doi:10.3892/mmr.2022.12871. https://pubmed.ncbi.nlm.nih.gov/36239258/

2. Zhu, Haixia, Wang, Hongxiang, Cheng, Yin, Wen, Zongzhuang, Gao, Jiangang. . Hadh deficiency induced oligoasthenoteratozoospermia through the TNF-α/Bcl-2 pathway in male mice. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 36, e22661. doi:10.1096/fj.202201144R. https://pubmed.ncbi.nlm.nih.gov/36398584/

3. Chu, Changbin, Liu, Shangjing, He, Zhiting, Zhao, Xueya, Li, Xi. 2024. HADH suppresses clear cell renal cell carcinoma progression through reduced NRF2-dependent glutathione synthesis. In Translational oncology, 49, 102112. doi:10.1016/j.tranon.2024.102112. https://pubmed.ncbi.nlm.nih.gov/39226735/