Description: Neointimal hyperplasia is the main cause of restenosis after percutaneous coronary interventions (PCIs). Both IFN- and macrophages play nonredundant roles in the pathogenesis of vascular intimal hyperplasia; however, the underlying mechanisms remain elusive and must be further investigated. In mouse peritoneal macrophages, IFN- significantly accelerated degradation and up-regulated polyubiquitination of liver X receptor (LXR)-α. Signal transducer and activator of transcription 1 (STAT1) inhibitor, fludarabine, and PIAS1 knockdown reduced ubiquitination and increased the expression of LXR-α in IFN-–treated macrophages. IFN- also increased the expression of endoplasmic reticulum (ER) stress–related proteins, including p-PERK, p-eIIF2α, and CCAAT-enhancer-binding protein homologous protein (CHOP), as well as apoptosis of macrophages. Treatment with ER stress inhibitor, 4-phenylbutyric acid (4-PBA), and LXR agonist, T0901317 (T0), alleviated IFN-–induced apoptosis in macrophages. Neointimal hyperplasia was significant after carotid ligation for 4 wk in ApoE –/– mice. IFN- mAb, T0, and 4-PBA treatment not only significantly attenuated neointimal hyperplasia but also decreased CD68 + TUNEL + double-positive macrophages in the hyperplastic neointima. Moreover, after 4-PBA or T0 administration, the number of CD68 + p-eIIF2α + and CD68 + CHOP + double-positive cells in neointimal was also apparently decreased. Taken together, these results defined an unexpected role of IFN- and LXR-α in the development of neointimal hyperplasia. The PIAS1/STAT1-dependent LXR-α degradation induced by IFN- promoted ER stress and apoptosis in macrophages, which leads to aggravated neointimal hyperplasia. LXR agonist efficiently improved neointimal hyperplasia, which may be a promising new strategy to ameliorate restenosis and vascular remodeling after PCI.—Zhao, Q., Zhou, D., You, H., Lou, B., Zhang, Y., Tian, Y., Guo, N., Chen, X., Liu, Y., Wu, Y., Yuan, Z., Zhou, J. IFN- aggravates neointimal hyperplasia by inducing endoplasmic reticulum stress and apoptosis in macrophages by promoting ubiquitin-dependent liver X receptor-α degradation.