Alox12, encoding arachidonic acid 12-lipoxygenase, acts on polyunsaturated fatty acid substrates to produce bioactive lipid mediators like eicosanes and lipoxins. It plays a significant role in inflammation, oxidation, and is associated with various biological pathways and diseases [8]. Genetic models, such as gene knockout mouse models, are valuable for studying its function.

In p53-mediated tumour suppression, Alox12 inactivation diminishes p53-mediated ferroptosis and p53-dependent inhibition of tumour growth in xenograft models, indicating its critical role in this distinct ferroptosis pathway [1]. In hepatic ischemia-reperfusion injury, blocking 12-HETE production, which is promoted by Alox12, inhibits liver dysfunction, inflammation, and cell death in mice and pigs [2]. In non-alcoholic steatohepatitis, a small molecule IMA-1 targeting the Alox12-ACC1 interaction ameliorates the disease in mice and macaques [3]. In acute liver injury, Gα12 overexpression exacerbates injury through ROCK1-mediated Alox12 dysregulation [4]. In cisplatin-induced acute kidney injury, baicalein alleviates injury by inhibiting Alox12-dependent ferroptosis [5]. In lung ischemia-reperfusion injury, Alox12-knockout mice show decreased ferroptosis, neutrophil extracellular trap formation, and tissue injury [6]. In myocardial ischemia-reperfusion injury, genetic inhibition of Alox12 protects mouse hearts from injury, while overexpression exacerbates it [7].

In conclusion, Alox12 is involved in multiple biological functions such as inflammation, oxidation, and ferroptosis. Gene knockout mouse models have been instrumental in revealing its role in diseases like tumour suppression, ischemia-reperfusion injuries in the liver, lung, and heart, as well as in non-alcoholic steatohepatitis, acute liver injury, and acute kidney injury. Understanding Alox12's function provides potential therapeutic targets for these disease areas.

References:

1. Chu, Bo, Kon, Ning, Chen, Delin, Tavana, Omid, Gu, Wei. 2019. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. In Nature cell biology, 21, 579-591. doi:10.1038/s41556-019-0305-6. https://pubmed.ncbi.nlm.nih.gov/30962574/

2. Zhang, Xiao-Jing, Cheng, Xu, Yan, Zhen-Zhen, She, Zhi-Gang, Li, Hongliang. 2017. An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury. In Nature medicine, 24, 73-83. doi:10.1038/nm.4451. https://pubmed.ncbi.nlm.nih.gov/29227475/

3. Zhang, Xiao-Jing, Ji, Yan-Xiao, Cheng, Xu, She, Zhi-Gang, Li, Hongliang. 2021. A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques. In Science translational medicine, 13, eabg8116. doi:10.1126/scitranslmed.abg8116. https://pubmed.ncbi.nlm.nih.gov/34910548/

4. Tak, Jihoon, Kim, Yun Seok, Kim, Tae Hyun, Hwang, Shin, Kim, Sang Geon. 2022. Gα12 overexpression in hepatocytes by ER stress exacerbates acute liver injury via ROCK1-mediated miR-15a and ALOX12 dysregulation. In Theranostics, 12, 1570-1588. doi:10.7150/thno.67722. https://pubmed.ncbi.nlm.nih.gov/35198058/

5. Guo, Shanshan, Zhou, Lang, Liu, Xueqi, Li, Yuanyuan, Wu, Yonggui. 2024. Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting ALOX12-dependent ferroptosis. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 130, 155757. doi:10.1016/j.phymed.2024.155757. https://pubmed.ncbi.nlm.nih.gov/38805781/

6. Li, Chongwu, Gao, Peigen, Zhuang, Fenghui, Wu, Junqi, Chen, Chang. 2024. Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia-Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Trap Formation. In Research (Washington, D.C.), 7, 0473. doi:10.34133/research.0473. https://pubmed.ncbi.nlm.nih.gov/39268501/

7. Zhang, Xiao-Jing, Liu, Xiaolan, Hu, Manli, Lu, Zhibing, Li, Hongliang. 2021. Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species. In Cell metabolism, 33, 2059-2075.e10. doi:10.1016/j.cmet.2021.08.014. https://pubmed.ncbi.nlm.nih.gov/34536344/

8. Zheng, Zhonghua, Li, Yin, Jin, Gehui, Zou, Mengsha, Duan, Shiwei. 2020. The biological role of arachidonic acid 12-lipoxygenase (ALOX12) in various human diseases. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 129, 110354. doi:10.1016/j.biopha.2020.110354. https://pubmed.ncbi.nlm.nih.gov/32540644/