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ABSTRACT The mitogen-activated protein kinase kinase 5 (MEK5)/extracellular signal-regulated kinase 5 (ERK5) axis has been reported to promote tumorigenesis in breast cancer (BC). Therefore, targeting the MEK5/ERK5 axis is a potential strategy against BC. BAY-885 is a novel inhibitor of ERK5; however, to date, its anti-tumor effects in BC have not been investigated. This study aimed to assess the anti-tumor effects of BAY-885 in BC and identify its underlying mechanisms of action. Unlike other ERK5 inhibitors, which frequently failed to mimic ERK5 genetic ablation phenotypes, the BAY-885 treatment effectively recapitulated ERK5 depletion effects in BC cells. Results revealed that BAY-885 affected the viability and induced apoptosis in BC cells. Moreover, the BAY-885-mediated downregulation of myeloid cell leukemia-1 (Mcl-1) and upregulation of Bim were dependent on ERK5 inhibition. Furthermore, BAY-885 triggered activation of endoplasmic reticulum (ER) stress, which further led to the upregulation of Bim and downregulation of Mcl-1. ER stress was induced in an ERK5 inhibition-dependent manner. These findings suggested that BAY-885 induced apoptosis in BC cells via ER stress/Mcl-1/Bim axis, suggesting that BAY-885 may serve as a therapeutic agent for BC. GRAPHICAL ABSTRACT