ALOX5, also known as arachidonate 5-lipoxygenase, is an important lipid metabolism enzyme. It converts arachidonic acid to leukotriene A4 (LTA4), participating in lipid-mediated signaling pathways, which are crucial in inflammation, cell death, and immune regulation processes [9]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In Huntington's disease, inactivation of the Alox5 gene abrogates ferroptosis activity in striatal neurons from HD mice, significantly ameliorating pathological phenotypes and extending their life spans, suggesting ALOX5 is critical for mHTT-mediated ferroptosis [1]. In Parkinson's disease, inhibition of ALOX5 protects dopaminergic neurons from ferroptosis, improving behavioral defects in PD mouse models [2]. In melanoma, down-regulation of ALOX5 is positively correlated with patient prognosis, and elevated ALOX5 promotes autophagy-dependent ferroptosis by activating the AMPK/mTOR pathway [3]. In intrahepatic cholangiocarcinoma, ALOX5 affects M2 macrophage infiltration in the tumor microenvironment, and targeting ALOX5 in combination with a CSF1R inhibitor reduces tumor volume [4]. In pancreatic cancer, ALOX5 regulates tumor-associated macrophage M2 polarization via the JAK/STAT pathway, and the ALOX5 inhibitor Zileuton can inhibit invasion and metastasis [5]. In bladder cancer, ALOX5 deficiency contributes to ferroptosis escape, and ALOX5 may be a therapeutic target and prognostic biomarker [6]. In glioma, ALOX5 promotes immunosuppressive M2 polarization and PD-L1 expression of glioma-associated microglia/macrophages, and an ALOX5-targeted nanobody shows anti-glioma efficacy [7]. In ovarian cancer, ALOX5 induces epithelial-to-mesenchymal transition (EMT) and promotes cell metastasis via the LTB4/BLT2/PI3K/AKT pathway [8]. In rheumatoid arthritis, knockdown or pharmacological inhibition of ALOX5 suppresses CD4+ T cell pyroptosis and improves symptoms in rodent models [9].

In conclusion, ALOX5 plays essential roles in multiple biological processes, especially in ferroptosis, immune microenvironment regulation, and cell metastasis. Studies using KO/CKO mouse models and other loss-of-function experiments have revealed its significance in various disease conditions, including neurodegenerative diseases, cancers, and rheumatoid arthritis, providing potential therapeutic targets for these diseases.