JMJD4 (jumonji domain containing 4) is a 2-oxoglutarate and iron-dependent dioxygenase that catalyzes protein hydroxylation with diverse physiological roles 1. Its primary function involves lysine hydroxylation of target proteins: it hydroxylates ETF1 at lysine-63 to promote translational termination efficiency, and hydroxylates PKM2 at lysine-66 to facilitate its chaperone-mediated autophagy degradation 2. JMJD4 also mediates demethylation of RIG-I at lysines 18 and 146, suppressing IL-6-STAT3 signaling and cholesterol synthesis 3. Clinically, JMJD4 demonstrates opposing roles in different disease contexts. In cardiac pathology, decreased JMJD4 expression contributes to dilated cardiomyopathy through PKM2 accumulation and impaired mitochondrial respiration 2, while JMJD4-mediated RIG-I demethylation protects against hepatic steatosis and both necroinflammation- and NASH-driven hepatocarcinogenesis 3. Conversely, elevated JMJD4 expression associates with poor prognosis in multiple cancers: colon adenocarcinoma 4, renal cell carcinoma 5, and lung cancer 6. JMJD4 promotes tumor progression by interacting with and suppressing PDCD5, thereby inhibiting TP53-dependent apoptosis and increasing chemoresistance 6. These findings position JMJD4 as a context-dependent therapeutic target amenable to small-molecule inhibition.