Multifaceted roles of CARM1 beyond histone arginine methylation

Coactivator-associated arginine methyltransferase 1 (CARM1), first identified in 1999, has been studied primarily for its nuclear role in epigenetic regulation through histone methylation. Subsequent research has expanded the substrate repertoire to include nonhistone proteins, thus uncovering broader functions in maintaining cellular homeostasis by regulating transcription, RNA processing, metabolism and organelle dynamics. More recently, CARM1 was shown to exert scaffolding functions independent of its catalytic activity, thereby orchestrating key signaling events involved in transcriptional activation, replication stress response and cell cycle control. These findings highlight the multifaceted roles of CARM1 in nuclear and cytoplasmic compartments. Despite substantial progress in the development of selective small-molecule inhibitors, their inability to target noncatalytic functions has limited their therapeutic potential. Consequently, novel strategies, such as proteolysis-targeting chimeras, are being explored to degrade the entire CARM1 protein, thereby abolishing its enzymatic and scaffolding functions. Here this review outlines the evolving functional landscape of CARM1, from its roles as a transcriptional coactivator to a multifunctional regulator of cellular homeostasis, with an emphasis on its enzyme-independent functions, thereby providing novel insights for next-generation therapeutic strategies.