Lta4h, short for Leukotriene A4 hydrolase, is a bifunctional zinc metallo-enzyme. It is classically known for its epoxide hydrolase activity that converts leukotriene A4 (LTA4) to the neutrophil chemoattractant LTB4, and also has aminopeptidase activity [4]. It is involved in the arachidonic acid (AA) metabolism pathway, a characteristic pathway in polyunsaturated fatty acid (PUFA) metabolism, and is associated with various biological processes and diseases [2]. Genetic models, such as knockout mouse models, have been crucial in understanding its functions.

In hepatocellular carcinoma (HCC), Lta4h deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206+ macrophage polarization, accelerating HCC progression. Mechanistically, Lta4h induces phosphorylation of heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), inhibiting its function in regulating Ltbp1 mRNA maturation in the nucleus [1]. In ovarian cancer, high expression of Lta4h is positively correlated with poor prognosis. Lta4h deficiency enhances sensitivity to Cisplatin and modifies immune cell infiltration characteristics [2]. In skin cancer, knocking out Lta4h significantly reduces skin cancer development in a mouse model, as Lta4h depletion induces cell cycle arrest at the G0/G1 phase by enhancing p27 protein stability [3].

In conclusion, Lta4h plays important roles in multiple biological processes and disease conditions. Gene knockout mouse models have revealed its functions in cancer development, such as in HCC, ovarian cancer, and skin cancer, highlighting its potential as a therapeutic target in these disease areas.

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. 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/

3. 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/

4. 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/