JMJD8 is an endoplasmic reticulum-localized jumonji C domain-containing protein that functions as a multifaceted regulator of inflammation, metabolism, and tumor biology. Primary function: JMJD8 acts as a positive regulator of TNF-induced NF-κB signaling 1 and regulates angiogenesis and cellular metabolism through PKM interaction 2. Mechanistically, JMJD8 localizes to the ER lumen and forms dimers/oligomers, potentially facilitating protein complex assembly 3. In cancer contexts, JMJD8 promotes glycolysis via PKM2 activation in colorectal cancer 4 and inhibits STING-TBK1 complex formation to suppress type I interferon responses in breast cancer, enabling immune evasion 5. JMJD8 also activates AKT phosphorylation through modulation of AKT methylation, promoting epithelial-mesenchymal transition 6. Disease relevance: JMJD8 emerges as a pan-cancer oncogene associated with genomic instability, DNA repair pathways, stemness, and immunosuppression, correlating with M2 macrophage infiltration and CD8+ T-cell depression 7. In metabolic diseases, JMJD8 drives adipocyte-intrinsic inflammation and insulin resistance through IRF3-dependent mechanisms and suppresses lipophagy via PLIN2 interaction [PMID:34686520; 80]. Clinical significance: JMJD8 represents a potential therapeutic target for cancer immunotherapy and metabolic disease treatment, with elevated expression in human tumors inversely correlating with antitumor immunity.