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Activation of ERK is critical for NaIO 3 -induced multiple signaling pathways to coordinate EMT in RPE cells. [Display omitted] • NaIO 3 was demonstrated to induce EMT in human ARPE-19 cells and in RPE cells of the mouse eyes as an AMD model. • Ca2+, EGFR, and ERK signaling pathways responded to NaIO 3 -induced EMT in ARPE-19 cells. • Post-treatment with FR180204 downregulated multiple NaIO 3 -induced signaling pathways leading to EMT. • ERK was shown to play a critical role in promoting oxidative stress-induced EMT of ARPE-19 cells in contrast to MEK. • FR180204 restored the RPE integrity and retinal morphology compromised by NaIO 3 in mouse retina. Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is related to the pathogenesis of various retinopathies including age-related macular degeneration (AMD). Oxidative stress is the major factor that induces degeneration of RPE cells associated with the etiology of AMD. Sodium iodate (NaIO 3) generates intracellular reactive oxygen species (ROS) and is widely used to establish a model of AMD due to the selective induction of retinal degeneration. This study was performed to clarify the effects of multiple NaIO 3 -stimulated signaling pathways on EMT in RPE cells. The EMT characteristics in NaIO 3 -treated human ARPE-19 cells and RPE cells of the mouse eyes were analyzed. Multiple oxidative stress-induced modulators were investigated and the effects of pre-treatment with Ca2+ chelator, extracellular signal-related kinase (ERK) inhibitor, or epidermal growth factor receptor (EGFR) inhibitor on NaIO 3 -induced EMT were determined. The efficacy of post-treatment with ERK inhibitor on the regulation of NaIO 3 -induced signaling pathways was dissected and its role in retinal thickness and morphology was evaluated by using histological cross-sections and spectral domain optical coherence tomography. We found that NaIO 3 induced EMT in ARPE-19 cells and in RPE cells of the mouse eyes. The intracellular ROS, Ca2+, endoplasmic reticulum (ER) stress marker, phospho-ERK, and phospho-EGFR were increased in NaIO 3 -stimulated cells. Our results showed that pre-treatment with Ca2+ chelator, ERK inhibitor, or EGFR inhibitor decreased NaIO 3 -induced EMT, interestingly, the inhibition of ERK displayed the most prominent effect. Furthermore, post-treatment with FR180204, a specific ERK inhibitor, reduced intracellular ROS and Ca2+ levels, downregulated phospho-EGFR and ER stress marker, attenuated EMT of RPE cells, and prevented structural disorder of the retina induced by NaIO 3. ERK is a crucial regulator of multiple NaIO 3 -induced signaling pathways that coordinate EMT program in RPE cells. Inhibition of ERK may be a potential therapeutic strategy for the treatment of AMD. [ABSTRACT FROM AUTHOR]