Protein arginine methyltransferase 5 orchestrates the homeostasis and reconstitution of intestinal stem cell niche via balancing urea cycling

Protein arginine methyltransferase 5 (PRMT5) is highly expressed in many cancers and is a potential therapeutic target. It is also expressed in the small intestine, suggesting a role in intestinal health. This study explores PRMT5’s function in both normal physiology and radiation-induced intestinal injury (RIII), focusing on its effects on intestinal stem cells (ISCs) and their niche. We examined PRMT5 expression in healthy and radiation-damaged intestines and treated mice and organoids with AMI-1, a PRMT5 inhibitor. Epithelial lineage composition, ISC proliferation, inducible nitric oxide synthase (iNOS) levels, and organoid activity were assessed. The impact of PRMT5 deficiency on ISC function was studied in vitro, and RNA-Seq and qRT-PCR were used to explore its effects on the urea cycle. PRMT5 was highly expressed in intestinal crypts. AMI-1 treatment reduced small intestine length, altered epithelial morphology, and increased secretory cells. In healthy intestines, PRMT5 inhibition enhanced Olfm4 + ISCs and induced iNOS expression. After radiation, PRMT5 deficiency inhibited ISC proliferation and caused Paneth cell acidification in the ISC niche. Organoids showed reduced vitality. PRMT5 deficiency disrupted the urea cycle, upregulated iNOS, increased NO production, and elevated lipid and ROS levels, impairing ISC homeostasis. PRMT5 is critical for maintaining intestinal homeostasis and regeneration. Its deficiency disrupts ISC niche function, highlighting PRMT5 as a potential target for treating intestinal disorders.