RASAL1 functions as a negative regulator of RAS signaling and acts as a tumor suppressor across multiple cancer types. 1 Mechanistically, RASAL1 suppresses RAS-GTP activity and downstream ERK1/2 phosphorylation, thereby restraining proliferative signaling. 2 Additionally, RASAL1 negatively regulates PI3K-AKT pathway activation, particularly when functioning alongside PTEN. 3 In normal physiology, RASAL1 also promotes dendrite formation in melanocytes and regulates fibrotic responses in endothelial and cardiac tissues. 4 Aberrant promoter hypermethylation represents a key mechanism of RASAL1 inactivation in gastric cancer, glaucomatous trabecular meshwork cells, and choriocarcinoma, occurring in 70%, elevated levels, and substantial frequencies respectively. 256 Reduced RASAL1 expression correlates with advanced tumor grade, increased invasive depth, and lymph node metastasis in gastric cancer. 1 In esophageal squamous cell carcinoma, RASAL1 participates in the MEST-PURA-ERK-snail signaling cascade regulating metastasis. 7 Notably, concurrent RASAL1 and PTEN alterations cooperatively activate PI3K-AKT signaling, promoting aggressive cancer phenotypes with substantially elevated progression and mortality rates. 3 RASAL1's downregulation through hypermethylation also contributes to cardiac fibrosis via endothelial-to-mesenchymal transition. 4 These findings establish RASAL1 as a critical multi-pathway tumor suppressor whose loss promotes cancer aggressiveness and organ fibrosis.