Remarkably, we report for the first time that As2O3 at physiologically relevant concentrations (effective in as low as ∼5 μM) induces the phosphorylation of ERK8 and activated ERK8 subsequently promotes the phosphorylation and degradation of IκBα, which leads to the activation of NF-κB and lung cancer cell apoptosis. Here, NFKBIA is linked to lung cancer.