SHROOM3 is an actin-binding protein that functions as a critical regulator of cell shape and cytoskeletal organization. Mechanistically, SHROOM3 promotes apical constriction in epithelial cells by facilitating F-actin and myosin II accumulation, and directs apicobasal microtubule assembly through gamma-tubulin redistribution 1. In the kidney, SHROOM3 is essential for podocyte integrity and glomerular filtration barrier maintenance; SHROOM3 deficiency impairs podocyte adhesion by downregulating focal adhesion molecules and stress fiber regulators, ultimately exacerbating proteinuria 1. SHROOM3 function extends to facial development, with pathogenic variants enriched in hemifacial microsomia patients 2. Genetically, SHROOM3 variants associate with multiple kidney diseases through distinct mechanisms. CKD-associated intronic variants promote renal fibrosis via SHROOM3-ROCK interaction through the ASD2 domain, activating TGFβ1 and Wnt/Ctnnb1 signaling in tubular cells and fibroblasts 3. Conversely, SHROOM3 appears protective against proteinuria, with genetic variants conferring reduced acute kidney injury risk 4. SHROOM3 variants also contribute to hypertension-induced ESRD 5. These pleiotropic effects suggest motif-specific functions: the ROCK-binding ASD2 domain mediates fibrosis, while distinct Fyn-binding motifs regulate proteinuria 6. Small molecule inhibitors targeting SHROOM3-ROCK interaction show therapeutic potential for mitigating kidney fibrosis.