NERATINIB markedly reduced vascular inflammation and atherosclerosis in mice by targeting ASK1, boosting effects with rosuvastatin.
Neratinib Flags Anti-Inflammatory Activity in Endothelial Cells
Atherosclerosis begins with endothelial dysfunction and lipid retention within the vessel wall, then progresses through sustained immune activation. Current options such as statins and PCSK9 inhibitors lower LDL-C, yet inflammatory activity can persist.
Researchers screened approved drugs using perturbational datasets generated from human endothelial cells stimulated with TNF-α and IL-1β. Neratinib emerged as a lead candidate, showing broad anti-inflammatory actions in endothelial cells. Follow-up experiments found that neratinib suppressed endothelial inflammation triggered by three distinct stimuli: TNF-α, IL-1β, and lipopolysaccharide.
Neratinib Acts Through ASK1, Not HER2
Mechanistic experiments suggested the anti-inflammatory effects were independent of neratinib’s classical HER2 or ERBB2 inhibition. Instead, the investigators reported that neratinib directly bound apoptosis signal-regulating kinase 1 (ASK1) and reduced ASK1 activation, positioning ASK1 signaling as a potential driver of the observed endothelial responses.
Neratinib Reduced Plaque Burden in Ldlr-/- Mice
To test in vivo relevance, the team treated male and female Ldlr-/- mice. Across sexes, neratinib was associated with lower plaque burden, smaller necrotic core size, and reduced macrophage infiltration within lesions, consistent with an attenuation of atherosclerotic progression in this preclinical model.
Combination With Rosuvastatin Improved Outcomes
The study also evaluated combination therapy with rosuvastatin, described as a standard lipid-lowering drug. Neratinib plus rosuvastatin produced superior antiatherosclerotic effects compared with statin monotherapy. A serum proteomics analysis further indicated that combination treatment reduced multiple inflammation-related cytokines and chemokines in the mouse model.
Together, these data support the concept that neratinib could be explored as a repurposed approach for vascular inflammation and atherosclerosis, with ASK1 identified as a candidate target in endothelial cells. The findings are preclinical and were generated in stimulated human endothelial cell systems and Ldlr-/- mouse models, including both male and female animals.
Reference: Zhang FS et al. Neratinib, a Clinical Drug Against Breast Cancer, Protects Against Vascular Inflammation and Atherosclerosis. Circulation Research. 2026;DOI: 10.1161/CIRCRESAHA.125.326508.
