JMJD5 regulates metabolism by hydroxylating ISY1, and regulating the Arginine Methyltransferase PRMT6

2-Oxoglutarate-dependent dioxygenases (2OGDDs) employ molecular oxygen, 2-oxoglutarate, and ferrous iron to catalyse two-ectron oxidations. This dependency enables some 2OGDD to act as sensors of cellular metabolic states, driving crucial functions when oxygen or metabolic homeostasis is perturbed, including adaptation to low oxygen, epigenetic control of gene transcription, and the reshaping of metabolic pathways. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), a 2OGDD that regulates epigenetic marks, is essential for DNA damage repair and is a key regulator of cell metabolism. Notably, JMJD5 is often reduced in hepatocellular carcinoma, correlating with poor overall survival. Despite its biological significance, the molecular functions of JMJD5 remain unresolved, and its physiological targets are elusive. Here, we identify and characterise a novel signalling pathway where JMJD5 hydroxylates an arginine residue on the protein ISY1. This modification enables ISY1 to bind to and reduce the activity of Protein Arginine N-methyltransferase 6 (PRMT6). Significantly, the inactivation of PRMT6 rescues the majority of the molecular phenotype driven by JMJD5 loss, establishing the JMJD5-ISY1-PRMT6 pathway as a principal executor of JMJD5’s enzymatic function. In a genetically engineered murine liver cancer model, JMJD5 loss suppressed tumour growth and rewired one-carbon, amino acid, and lipid metabolism, recapitulating the network-level changes observed in human HCC cells. This signalling pathway clarifies existing controversies regarding JMJD5’s function and identifies PRMT6 as a potential therapeutic target for treating cancers that lack JMJD5.