EHHADH, also known as enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase or peroxisomal L-bifunctional protein, is an enzyme in the classic peroxisomal fatty acid β-oxidation pathway. It catalyzes the second and third step of this pathway, playing a crucial role in fatty acid metabolism [2,3,5,7,8,9]. This pathway is vital for energy production and maintaining cellular metabolic homeostasis. Genetic models, such as gene knockout mouse models, have been instrumental in studying EHHADH's functions.

In EHHADH knockout mice, there is worsened renal tubular injury in diabetic mice, and male-specific kidney hypertrophy and glomerular filtration rate reduction in adult mice, along with metabolite changes consistent with peroxisomal dysfunction [1,9]. In renal tubular epithelial cells in vitro, knockdown of EHHADH induced peroxisome loss, which was restored by autophagic inhibitors, indicating its role as a modulator of pexophagy [1]. In hepatocellular carcinoma, EHHADH expression is down-regulated and related to TP53 mutation, hepatocyte de-differentiation, and ferroptosis escape [3]. In osteosarcoma, EHHADH overexpression is associated with poor survival, and its knockdown suppresses tumor cell proliferation [4]. In bladder cancer, EHHADH contributes to cisplatin resistance, being directly regulated by miRNA-486-5p [6].

In conclusion, EHHADH is essential for peroxisomal fatty acid β-oxidation and plays significant roles in multiple biological processes and disease conditions. Gene knockout mouse models have been key in revealing its functions in diseases like diabetic kidney disease, male-specific kidney pathologies, hepatocellular carcinoma, osteosarcoma, and bladder cancer, enhancing our understanding of disease mechanisms and potentially providing new therapeutic targets.

References:

1. Kan, Shuyan, Hou, Qing, Shi, Jinsong, Liu, Zhihong, Jiang, Song. 2024. EHHADH deficiency regulates pexophagy and accelerates tubulointerstitial injury in diabetic kidney disease. In Cell death discovery, 10, 289. doi:10.1038/s41420-024-02066-4. https://pubmed.ncbi.nlm.nih.gov/38879653/

2. Park, Hee-Seon, Song, Ji-Won, Park, Jin-Ho, Won, Young-Suk, Kwon, Hyo-Jung. 2020. TXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation. In Autophagy, 17, 2549-2564. doi:10.1080/15548627.2020.1834711. https://pubmed.ncbi.nlm.nih.gov/33190588/

3. Xie, S, Li, M, Jiang, F, Yi, Q, Yang, W. . [EHHADH is a key gene in fatty acid metabolism pathways in hepatocellular carcinoma: a transcriptomic analysis]. In Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 43, 680-693. doi:10.12122/j.issn.1673-4254.2023.05.02. https://pubmed.ncbi.nlm.nih.gov/37313808/

4. Cui, Juncheng, Yi, Guoliang, Li, Jinxin, Li, Yangtao, Qian, Dongyang. 2021. Increased EHHADH Expression Predicting Poor Survival of Osteosarcoma by Integrating Weighted Gene Coexpression Network Analysis and Experimental Validation. In BioMed research international, 2021, 9917060. doi:10.1155/2021/9917060. https://pubmed.ncbi.nlm.nih.gov/33997049/

5. Forst, Anna-Lena, Reichold, Markus, Kleta, Robert, Warth, Richard. 2021. Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM. In Frontiers in physiology, 12, 715485. doi:10.3389/fphys.2021.715485. https://pubmed.ncbi.nlm.nih.gov/34349672/

6. Okamura, Shunsuke, Yoshino, Hirofumi, Kuroshima, Kazuki, Nakagawa, Masayuki, Enokida, Hideki. 2021. EHHADH contributes to cisplatin resistance through regulation by tumor-suppressive microRNAs in bladder cancer. In BMC cancer, 21, 48. doi:10.1186/s12885-020-07717-0. https://pubmed.ncbi.nlm.nih.gov/33430801/

7. Zhao, Shimin, Xu, Wei, Jiang, Wenqing, Xiong, Yue, Guan, Kun-Liang. . Regulation of cellular metabolism by protein lysine acetylation. In Science (New York, N.Y.), 327, 1000-4. doi:10.1126/science.1179689. https://pubmed.ncbi.nlm.nih.gov/20167786/

8. Zhang, Yuan, Chen, Yuling, Zhang, Zhao, Zhao, Jianyuan, Zhou, Xiangyu. 2022. Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice. In Cell death & disease, 13, 279. doi:10.1038/s41419-022-04725-9. https://pubmed.ncbi.nlm.nih.gov/35351852/

9. Ranea-Robles, Pablo, Portman, Kensey, Bender, Aaron, Argmann, Carmen, Houten, Sander M. 2021. Peroxisomal L-bifunctional protein (EHHADH) deficiency causes male-specific kidney hypertrophy and proximal tubular injury in mice. In Kidney360, 2, 1441-1454. doi:10.34067/KID.0003772021. https://pubmed.ncbi.nlm.nih.gov/34651140/