The Two Faces of ZEB1: A Tumor-Promoting Protein in Cancer Cells that Protects Against Inflammation in Macrophages

The protein ZEB1 is best known for regulating cell plasticity and endowing cancer cells with a more aggressive phenotype. Interestingly, two new studies show that ZEB1 expression in macrophages has a protective role against inflammation and atherosclerosis. Inflammation is a natural response against infection and tissue injury but can evolve toward chronic inflammation if not resolved properly. The first study (Nat Commun, 14:7471) shows that ZEB1 promotes inflammation resolution and safeguards against chronic autoimmune inflammation by reducing the mitochondrial content, which are the structures that generate most of the energy needed by cells. The second study (Nat Commun 14:8316) shows that ZEB1 expression in macrophages enhances the trafficking of lipids inside cells. Eliminating ZEB1 in macrophages exacerbates atherosclerosis in mice and increases their lipids and inflammatory markers in the blood. Lower ZEB1 expression in human atherosclerotic plaques correlates with an increased risk of stroke and myocardial infarction. Importantly, nanoparticles containing ZEB1 reduce atherosclerosis in mice. These studies reveal that modulating ZEB1 could be a potential therapeutic strategy in dysregulated inflammation and atherosclerosis.