A focus on c-Jun-N-terminal kinase signaling in sepsis-associated multiple organ dysfunction: Mechanisms and therapeutic strategies.

Sepsis is a life-threatening condition characterized by a widespread inflammatory response to infection, inevitably leading to multiple organ dysfunctions. Extensive research, both in vivo and in vitro, has revealed key factors contributing to sepsis, such as apoptosis, inflammation, cytokine release, oxidative stress, and systemic stress. The changes observed during sepsis-induced conditions are mainly attributed to altered signal transduction pathways, which play a critical role in cell proliferation, migration, and apoptosis. C-Jun N-terminal kinases, JNKs, and serine/threonine protein kinases in the mitogen-activated super family have gained considerable interest for their contribution to cellular events under sepsis conditions. JNK1 and JNK2 are present in various tissues like the lungs, liver, and intestine, while JNK3 is found in neurons. The JNK pathway plays a crucial role in the signal transduction of cytokines related to sepsis development, notably TNF-α and IL-1β. Activated JNK leads to apoptosis, causing tissue damage and organ dysfunction. Further, JNK activation is significant in several inflammatory conditions. Pharmacologically inhibiting JNK has been shown to prevent sepsis-associated damage across multiple organs, including the lungs, liver, intestines, heart, and kidneys. Multiple signaling pathways have been implicated in sepsis, including JNK/c-Myc, Mst1-JNK, MKK4-JNK, JNK-dependent autophagy, and Sirt1/FoxO3a. The review examines the role of JNK signaling in the development of sepsis-induced multiple-organ dysfunction through specific mechanisms. It also discusses different therapeutic approaches to target JNK. This review emphasizes the potential of JNKs as targets for the development of therapeutic agents for sepsis and the associated specific organ damage.