ArticleJCI insight2024
12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Comparative proteomic analysis of skin wound healing responses to biomaterial treatments identifies key pathways which govern differential regenerative outcomes.Biomaterials · 2026Article
- Using animal models to decipher the role of polyamines in the pancreas and β Cell.Amino acids · 2026Review
- Polyphenol-Enriched Fraction from Chestnut Shells as a Source of Bioactive Compounds for Friedreich Ataxia.Molecules (Basel, Switzerland) · 2025Article
- Macrophage-mediated metabolic dysregulation in the pancreas: Insights from obesity.World journal of biological chemistry · 2025Review
- Dysregulated Resolution of Inflammation After Respiratory Viral Infections: Molecular Pathways Linking Neuroinflammation to Post-Viral Neuropathic Pain-A Narrative Review.International journal of molecular sciences · 2025Review
- The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.Cell communication and signaling : CCS · 2025Article
- 12-Lipoxygenase Inhibition Improves Glycemia and Obesity-associated Inflammation in Male Human Gene Replacement Mice.Endocrinology · 2025Article
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15 authors.
Funding
Abstract
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages, with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift toward an immunosuppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in IFN response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.