Mitogen-activated protein kinase signaling and drug-induced liver injury: A molecular connection

Drug-induced liver injury (DILI) is a global health concern and one of the leading causes for the withdrawal of drugs from the market. DILI can exacerbate chronic liver injury to acute or chronic liver failure. The mitogen-activated protein kinase (MAPK) signaling cascade is the most conserved pathway that regulates key physiological processes, including cell proliferation, differentiation, inflammation, stress responses, and apoptosis. MAPK pathways such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 are activated by growth factors, cytokines and oxidative stress-related signaling. Increasing evidence indicates that drug metabolism-induced reactive oxygen species (ROS) can activate MAPK pathways such as ERK, JNK, and p38 MAPK in hepatocytes. Activation of MAPK through phosphorylation contributes to necrosis and apoptosis, mitochondrial toxicity, oxidative stress, inflammation, and impaired autophagy. MAPK activation can also stimulate nuclear factor-κB (NF-κB)-mediated inflammatory signaling, thereby amplifying liver injury. While the role of MAPK signaling in acetaminophen-induced hepatotoxicity is well established, emerging studies indicate that several classes of drugs can also trigger MAPK-mediated liver injury. In this context, the present review aimed to summarize the current understanding of MAPK signaling pathways involved in the pathogenesis of DILI, emphasis the roles of ERK, JNK, and p38 pathways in mediating oxidative stress, inflammation, and hepatocyte death. Understanding these mechanisms may help identify potential therapeutic targets and guide future clinical strategies for the prevention and management of DILI.