SARAF (store-operated calcium entry associated regulatory factor) is a negative regulator of store-operated Ca2+ entry (SOCE) that protects cells from pathological calcium overload. Mechanistically, SARAF functions as an endoplasmic reticulum membrane protein that mediates slow Ca2+-dependent inactivation (SCDI) of CRAC channels by facilitating STIM1-Orai1 decoupling following ER calcium refilling 1. Upon physiological Ca2+ elevation, SARAF translocates to plasma membrane-ER junctions in a STIM1-dependent manner to promote Orai1 channel closure within PI(4,5)P2-rich microdomains 2. Dysregulation of SARAF has significant disease implications. In acute pancreatitis, SARAF levels initially increase but are subsequently degraded, resulting in excessive Ca2+ influx and acinar cell damage; SARAF knockout mice develop more severe pancreatitis, while SARAF overexpression provides protective effects 3. In neonatal platelets, SARAF overexpression impairs thrombin-induced Ca2+ homeostasis, contributing to reduced platelet responses 4. Additionally, the SARAF-miR-155-5p axis may mediate beneficial effects of cholecalciferol supplementation in multiple sclerosis by regulating calcium-release-activated channels 5. SARAF represents a potential therapeutic target for conditions characterized by pathological calcium overload.