ALOX15B

Somatic mutations contribute to cancer development by altering the activity of enhancers. In the study, a total of 135 mutation-driven enhancers, which displayed significant chromatin accessibility changes, were identified as candidate risk factors for breast cancer (BRCA). Furthermore, we identified four mutation-driven enhancers as independent prognostic factors for BRCA subtypes. In Her2 subtype, enhancer G > C mutation was associated with poorer prognosis through influencing its potential target genes FBXW9, TRIR, and WDR83. We identified aminoglutethimide and quinpirole as candidate drugs targeting the mutated enhancer. In normal subtype, enhancer G > A mutation was associated with poorer prognosis through influencing its target genes ALOX15B, LINC00324, and MPDU1. We identified eight candidate drugs such as erastin, colforsin, and STOCK1N-35874 targeting the mutated enhancer. Our findings suggest that somatic mutations contribute to breast cancer subtype progression by altering enhancer activity, which could be potential candidates for cancer therapy.

The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.

The neural cell death in cerebral infarction is suggested to be ferroptosis-like cell death, involving the participation of 15-lipoxygenase. Ferroptosis is induced by lipid radical species generated through the one-electron reduction of lipid hydroperoxides, and it has been shown to propagate intracellularly and intercellularly. At lower oxygen concentration, it appeared that both regiospecificity and stereospecificity of conjugated diene moiety in lipoxygenase-catalysed lipid hydroperoxidation are drastically lost. As a result, in the reaction with linoleic acid, the linoleate 9-peroxyl radical-ferrous lipoxygenase complex dissolves into the linoleate 9-peroxyl radical and ferrous 15-lipoxygenase. Subsequently, the ferrous 15-lipoxygenase then undergoes one-electron reduction of 13-hydroperoxy octadecadienoic acid, generating an alkoxyl radical (Pseudoperoxidase reaction). A part of the produced lipid alkoxyl radicals undergoes cleavage of C-C bonds, liberating small molecular hydrocarbon radicals. Particularly, in ω-3 polyunsaturated fatty acids, which are abundant in the vascular and nervous systems, the liberation of small molecular hydrocarbon radicals was more pronounced compared to ω-6 polyunsaturated fatty acids. The involvement of these small molecular hydrocarbon radicals in the propagation of membrane lipid damage is suggested.