Lta4h, or leukotriene A4 hydrolase, is a bifunctional zinc metallo-enzyme. It is classically known for its epoxide hydrolase activity, converting leukotriene A4 to the neutrophil chemoattractant LTB4, and also has aminopeptidase activity [7]. Lta4h is involved in the arachidonic acid metabolism pathway, which is a characteristic pathway in polyunsaturated fatty acid metabolism [8]. It has been associated with various biological processes and diseases, such as inflammation, cancer, and tuberculosis [1,2,3,4,5,6,8]. Genetic models, like gene knockout (KO) mouse models, are valuable for studying its functions.

In hepatocellular carcinoma (HCC), Lta4h deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206+ macrophage polarization through up-regulating LTBP1 expression and downstream TGF-β secretion and activation. Lta4h-deficient patients have poor prognosis and immunotherapy resistance [1]. In skin cancer, knocking out Lta4h significantly reduces skin cancer development in a two-stage skin cancer mouse model by inducing cell cycle arrest at the G0/G1 phase through enhancing p27 protein stability [5]. In ovarian cancer, deficiency of Lta4h enhances sensitivity to Cisplatin and modifies the characteristics of immune cell infiltration [8].

In conclusion, Lta4h plays crucial roles in multiple biological processes and disease conditions. KO mouse models have revealed its significance in cancer development, microenvironment regulation, and response to therapies in HCC, skin cancer, and ovarian cancer. Understanding Lta4h functions can potentially provide new diagnostic and therapeutic strategies for related diseases.

References:

1. Yang, Shuai, Qiu, Xinyao, Yang, Yingcheng, Wang, Hongyang, Chen, Lei. 2025. LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis. In Cell reports. Medicine, 6, 102000. doi:10.1016/j.xcrm.2025.102000. https://pubmed.ncbi.nlm.nih.gov/40056904/

2. Ren, Tianjiao, Wang, Song, Zhang, Bo, Zhao, Xiaorui, Feng, Juan. 2023. LTA4H extensively associates with mRNAs and lncRNAs indicative of its novel regulatory targets. In PeerJ, 11, e14875. doi:10.7717/peerj.14875. https://pubmed.ncbi.nlm.nih.gov/36923505/

3. Cherian, Ajith, Ajitha, Kesi Chellappan, Iype, Thomas, Divya, K P. 2021. Neurotuberculosis: an update. In Acta neurologica Belgica, 121, 11-21. doi:10.1007/s13760-020-01575-0. https://pubmed.ncbi.nlm.nih.gov/33400226/

4. Siddiqi, Omar K, Ghebremichael, Musie, Musukuma, Kalo, Atadzhanov, Masharip, Koralnik, Igor J. 2021. LTA4H Prevalence and Mortality in Adult Zambians with Tuberculous Meningitis. In Annals of neurology, 90, 994-998. doi:10.1002/ana.26240. https://pubmed.ncbi.nlm.nih.gov/34595756/

5. Oi, Naomi, Yamamoto, Hiroyuki, Langfald, Alyssa, Bode, Ann M, Dong, Zigang. . LTA4H regulates cell cycle and skin carcinogenesis. In Carcinogenesis, 38, 728-737. doi:10.1093/carcin/bgx049. https://pubmed.ncbi.nlm.nih.gov/28575166/

6. Zhao, Simin, Yao, Ke, Li, Dan, Guo, Zhiping, Dong, Zigang. 2019. Inhibition of LTA4H by bestatin in human and mouse colorectal cancer. In EBioMedicine, 44, 361-374. doi:10.1016/j.ebiom.2019.05.008. https://pubmed.ncbi.nlm.nih.gov/31085102/

7. Xu, Xin, Li, Jin-Dong, Green, Todd J, Blalock, J Edwin, Gaggar, Amit. 2024. Neutrophil elastase-dependent cleavage of LTA4H alters its aminopeptidase activity in cystic fibrosis. In The European respiratory journal, 63, . doi:10.1183/13993003.01512-2023. https://pubmed.ncbi.nlm.nih.gov/38387968/

8. Guo, Zhengyang, Huang, Jiaqi, Huo, Xiao, Yang, Jianling, Xue, Lixiang. 2024. Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin. In Science China. Life sciences, 67, 1226-1241. doi:10.1007/s11427-023-2444-5. https://pubmed.ncbi.nlm.nih.gov/38300441/