MAPK/ERK signaling pathway in rheumatoid arthritis: mechanisms and therapeutic potential

Rheumatoid arthritis (RA) is a multifaced autoimmune disorder characterized by chronic joint inflammation, leading to progressive disability and significantly impacting patients' quality of life. Despite advances in treatment, finding a cure or preventing disease progression remains a major clinical challenge, underscoring the urgent need for novel therapeutic strategies. Among various pathways involved in the pathophysiology of RA, the mitogen-activated protein kinases/extracellular regulated protein kinases (MAPK/ERK) pathway is of particular importance. As the central cascade within the broader MAPK signaling pathways, MAPK/ERK plays a critical role in regulating numerous physiological and pathological processes, with a well-established and prominent involvement in RA. Unlike p38 MAPK and c-Jun-N-terminal kinase (JNK), whose role in RA have been well-documented, the specific contributions of the MAPK/ERK pathway to RA remains comprehensively unreviewed. Furthermore, the MAPK/ERK pathway does not act in isolation but interacts synergistically with other major pathways, including NF-κB, Janus kinase-signal transducer and activator of transcription (JAK/STAT), sonic hedgehog (SHH), and PI3K/AKT, which further enhance its pathological effects. This review offers a comprehensive analysis of MAPK/ERK signaling pathway, focusing on its molecular components and its contribution to RA pathophysiology. Furthermore, we explore the cross-talk between MAPK/ERK and other pathways in the context of RA, and evaluates the therapeutic potential of targeting this pathway with small molecule inhibitors, natural compounds and biomolecules. By elucidating the mechanistic role of MAPK/ERK in RA, this article aims to highlight the pathway's therapeutic relevance and provide a foundation for the developing more effective, targeted therapies for RA.