PRMT1 and its Substrates: Novel functions in kidney and metabolic diseases

Protein arginine methyltransferase 1 (PRMT1) is best known as a nuclear epigenetic writer that deposits the activating H4R3me2a mark. However, PRMT1 also methylates diverse non‑histone substrates across multiple cellular compartments, and this review moves beyond chromatin‑centric models to provide a substrate‑driven mechanistic framework in kidney and metabolic diseases. We analyze four validated substrate axes: FoxO1 in gluconeogenesis, BRD4 in fibrosis, UBE2m in fatty acid metabolism, and RelA in inflammation. These examples illustrate how PRMT1 integrates metabolic, inflammatory and fibrotic signals in a cell‑type‑specific manner. A key insight is functional pleiotropy: PRMT1 exerts opposing roles-restraining lipolysis in white adipose tissue while enabling thermogenesis in brown fat, and suppressing NF‑κB in renal tubules while promoting pro‑inflammatory macrophage polarization in the liver. This complexity challenges the view of PRMT1 as uniformly pro‑pathogenic. We critically evaluate the inhibitor landscape, including the terminated clinical trial of GSK3368715, and identify major translational barriers. We conclude that realizing therapeutic potential in chronic kidney and metabolic diseases requires a shift from broad inhibition toward context‑selective modulation-through substrate‑selective inhibitors, tissue‑specific delivery and biomarker‑guided strategies.