SMTNL2 (smoothelin-like 2) is an actin-binding protein that regulates cytoskeletal dynamics during epithelial development and differentiation. Structurally, SMTNL2 contains an N-terminal coiled-coil region and a C-terminal calponin homology domain characteristic of the smoothelin protein family 1. In epithelial tissues, SMTNL2 localizes to the apical and junctional actin cortex, where it stabilizes the dense apical actin cytoskeleton by inhibiting coronin-1B-mediated actin turnover 2. This stabilization is essential for proper epithelial morphogenesis; SMTNL2 deficiency results in membrane herniations and cortical abnormalities 2. SMTNL2 functions as a JNK substrate with a conserved docking site (residues 180-193) that enables high-affinity binding to JNK1-3 and phosphorylation at multiple sites 3. The protein is highly expressed in skeletal muscle and induced during myocyte differentiation 3. Clinically, SMTNL2 methylation patterns in urine sediment serve as a biomarker for renal proximal tubular cell injury in diabetic kidney disease, correlating with declining glomerular filtration rate 4. Additionally, SMTNL2 has been identified as part of a glutamine metabolism-related prognostic signature in clear cell renal cell carcinoma 5, and genetic variants near SMTNL2 associate with rheumatoid arthritis susceptibility in Arab populations 6.