Alox12-flox Mouse

Alox12, also known as arachidonate 12-lipoxygenase, acts on polyunsaturated fatty acid substrates to produce bioactive lipid mediators like eicosanes and lipoxins. It plays a crucial role in inflammation and oxidation processes, and is involved in multiple biological pathways related to various diseases [9].

In p53-mediated tumour suppression, Alox12 inactivation diminishes p53-mediated ferroptosis and abrogates p53-dependent inhibition of tumour growth in xenograft models, suggesting it is critical for this process [1]. In hepatic ischemia-reperfusion injury, the ALOX12-12-HETE-GPR31 signaling axis is a key determinant, and blocking 12-HETE production (regulated by Alox12) can attenuate liver damage [2]. In non-alcoholic steatohepatitis (NASH), a small molecule IMA-1 that interrupts the Alox12-ACC1 interaction can treat NASH in mice and macaques [3]. Gα12 overexpression in hepatocytes by ER stress exacerbates acute liver injury via ROCK1-mediated dysregulation of Alox12 [4]. Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting Alox12-dependent ferroptosis [5]. In hepatic ischemia-reperfusion injury, TRPM2-mediated calcium influx increases Alox12 expression, leading to mitochondrial lipid peroxidation [6]. In lung ischemia-reperfusion injury, Alox12 and its metabolite 12-HETE promote ferroptosis and neutrophil extracellular trap formation, and Alox12-knockout mice show decreased injury [7]. In myocardial ischemia-reperfusion injury, genetic inhibition of Alox12 protects mouse hearts, while pharmacological inhibition reduces cardiac injury in multiple species [8]. In diabetic kidney disease, Alox12 levels in renal tissue are elevated and can predict disease progression [10].

In conclusion, Alox12 is involved in multiple biological processes, especially those related to ferroptosis, inflammation, and lipid peroxidation. Gene-knockout mouse models have been instrumental in revealing its role in various disease conditions such as cancer, ischemia-reperfusion injuries, and diabetic kidney disease, providing potential therapeutic targets for these diseases.