Alox15, also known as 15-lipoxygenase-1 or 12/15-lipoxygenase (12/15-LOX), is an enzyme that oxidizes polyunsaturated fatty acids, especially omega-6 and-3 fatty acids, to produce bioactive lipid metabolites. It is involved in oxidative and inflammatory responses, and its metabolites can influence the expression of various genes and cytokine production related to inflammation and its resolution [2].

In myocardial ischemia-reperfusion (I/R) injury, studies using a left anterior descending coronary artery ligation mouse model found that Alox15 expression increases specifically in the injured area of the left ventricle, and myocardial-specific knockout of Alox15 alleviates I/R injury and restores cardiac function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an Alox15-derived metabolite, promotes cardiomyocyte ferroptosis during prolonged reperfusion [1]. In asthma, experiments in an HDM/LPS-induced allergic airway inflammation mouse model and in HDM/LPS-stimulated 16HBE cells showed that ALOX15-induced lipid peroxidation increases the susceptibility to ferroptosis in asthmatic epithelial cells, and silencing ALOX15 decreases ferroptosis [3]. In cervical cancer, macrophage-derived exosomes containing miRNA-660-5p can attenuate ALOX15 expression in cancer cells to suppress ferroptosis, and ALOX15 is positively associated with a good prognosis [4].

In summary, Alox15 plays a significant role in various biological processes, especially in inflammation-related diseases. Gene knockout models, such as the myocardial-specific knockout of Alox15 in mice, have been crucial in revealing its role in diseases like myocardial I/R injury, asthma, and cervical cancer, providing potential therapeutic targets for these conditions.

References:

1. Cai, Wenbin, Liu, Le, Shi, Xuelian, Zhu, Yi, Zhang, Xu. 2023. Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis. In Circulation, 147, 1444-1460. doi:10.1161/CIRCULATIONAHA.122.060257. https://pubmed.ncbi.nlm.nih.gov/36987924/

2. Singh, Nikhlesh K, Rao, Gadiparthi N. 2018. Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. In Progress in lipid research, 73, 28-45. doi:10.1016/j.plipres.2018.11.001. https://pubmed.ncbi.nlm.nih.gov/30472260/

3. Zhang, Weizhen, Huang, Fangfang, Ding, Xuexuan, Wang, Wenjian, Luo, Lianxiang. 2024. Identifying ALOX15-initiated lipid peroxidation increases susceptibility to ferroptosis in asthma epithelial cells. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167176. doi:10.1016/j.bbadis.2024.167176. https://pubmed.ncbi.nlm.nih.gov/38641013/

4. Luo, Yanlin, Chen, Yibing, Jin, Huan, Liu, Quentin, Zou, Zhengzhi. 2023. The suppression of cervical cancer ferroptosis by macrophages: The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes. In Acta pharmaceutica Sinica. B, 13, 2645-2662. doi:10.1016/j.apsb.2023.03.025. https://pubmed.ncbi.nlm.nih.gov/37425043/