MAPK8 (mitogen-activated protein kinase 8), also known as JNK1, is a serine/threonine kinase that functions as a key signaling hub in cellular stress responses and inflammatory pathways. 1 MAPK8 displays multiple isoforms with distinct substrate binding patterns, where the beta-1 isoform preferentially binds c-Jun, while alpha and other isoforms show lower affinity for both c-Jun and ATF2 transcription factors, though all isoforms achieve similar phosphorylation efficiency. 2 In neuropathic pain, MAPK8 phosphorylation (p-MAPK8/JNK) mediates neuroinflammatory responses by promoting TRAF6 binding to ubiquitinated proteins and activating NF-κB signaling, suggesting autophagy-mediated regulation of MAPK8 activity modulates pain maintenance. 3 MAPK8 functions within the MAPK8/FOXO3 signaling pathway to regulate autophagy and mitophagy in bone cells, contributing to homeostasis in osteoblasts and osteoclasts. 4 In polycystic ovary syndrome, MAPK8/JNK participates in autophagy-related pathophysiology affecting ovarian follicular development. 1 Network analysis identifies MAPK8 as a central hub in rheumatoid arthritis pathogenesis, where naringin-mediated inhibition of MAPK8 phosphorylation suppresses inflammatory cytokine production and promotes fibroblast-like synoviocyte apoptosis. These findings establish MAPK8 as a critical regulator of inflammation, autophagy, and cellular stress responses across multiple disease contexts.