The mitogen-activated protein kinase (MAPK) pathways, ERK, JNK, and p38, are key regulators of immune responses during viral infections. These signaling cascades control cytokine production, T cell activity, and antigen presentation. However, many viruses can hijack MAPK pathways to avoid immune detection, promote their replication, and establish chronic infection. In this review, we discuss how different viruses, including HSV-1, HBV, HCMV, and SARS-CoV-2, manipulate MAPK signaling to alter host cell functions. A particular focus is given to the CD1d–iNKT cell axis, which plays a critical role in early antiviral responses but is often disrupted through MAPK-dependent mechanisms. We explore how changes in MAPK signaling affect antigen-presenting cells, drive T cell exhaustion, and reprogram immune cell metabolism, factors that contribute to viral immune evasion. The review also examines therapeutic strategies aimed at targeting MAPKs to improve antiviral immunity. These include small-molecule inhibitors and immune modulators that may enhance antiviral responses while limiting side effects. We emphasize the importance of context, as MAPK-targeted therapies must be carefully timed and tailored to avoid suppressing protective immunity or triggering unwanted inflammation. Overall, this review highlights the therapeutic potential and challenges of targeting MAPK pathways in viral infections and encourages further research into selective, host-directed antiviral strategies.
Khan et al. (Fri,) studied this question.