PPP1R18 (protein phosphatase 1 regulatory subunit 18), also known as Phostensin, is a regulatory subunit that targets protein phosphatase 1 (PP1) to the actin cytoskeleton and participates in critical cellular functions. 1 PPP1R18 localizes to the nucleus and actin ring structures, where it regulates actin organization and podosome formation. 2 At the molecular level, PPP1R18 dephosphorylates Rap1 GTPase to stabilize the Mig-10/RIAM/Lamellipodin-integrin-talin complex, enabling lymphocyte integrin activation. 3 In esophageal squamous cell carcinoma, PPP1R18 promotes tumor progression through calcineurin-mediated ERK pathway activation rather than PP1 binding, correlating with increased metastasis and reduced survival. 1 PPP1R18 overexpression inhibits osteoclast differentiation and bone resorption, while knockdown promotes these processes, indicating roles in bone homeostasis. Clinically, PPP1R18 deletion in mice reduces integrin-mediated lymphocyte functions and ameliorates T cell-mediated colitis. 2 Epigenetically, PPP1R18 methylation associates with type 2 diabetes, chr6 hepatitis B fibrosis progression, and schizophrenia spectrum disorders. 456 These findings suggest PPP1R18 represents a multifunctional regulator with therapeutic potential in cancer, inflammatory, and metabolic diseases.