The mitogen-activated protein kinase (MAPK) pathway transmits signals from the cell surface to the nucleus involved in the infection of CoVs such as MHV [36] and SARS-CoV [37]. CQ could inhibit HCoV-229E replication in human embryonic lung epithelial cells (L132) through suppressing the activation of p38 MAPK [38]. Moreover, HCQ could markedly induce the production of cellular reactive oxygen species (ROS), which play an important role in the activation of innate immunity [39]. HCQ also could trigger the host defense mechanism through the mitochondrial antiviral signaling (MAVS) pathway, resulting in anti-dengue virus activity [39]. Therefore, CQ/HCQ may also exert their antiviral activity by suppressing the activation of p38 MAPK pathway and affecting the host defense machinery (Figure 1).