SDF4 (stromal cell-derived factor 4) is a calcium-binding protein primarily localized to the endoplasmic reticulum (ER) that plays multifaceted roles in cellular stress responses and disease progression. 1 Functionally, SDF4 is involved in ER stress regulation and the unfolded protein response, with emerging evidence linking it to secretory protein trafficking. 2 In the context of diabetic foot ulcers, SDF4 operates downstream of the FOXM1/GAS5 signaling axis to suppress ER stress, reduce cell apoptosis, and promote angiogenesis in endothelial cells. 3 SDF4 serves as a prognostic biomarker for sepsis mortality, where decreased expression correlates with excessive ER stress and poor patient outcomes, while overexpression attenuates ER stress in murine models. Clinically, SDF4 demonstrates significant diagnostic and prognostic value across multiple malignancies. 4 Serum SDF4 levels distinguish gastric cancer patients from healthy controls with 89% sensitivity and 99% specificity, and are elevated even in early-stage disease. 5 SDF4 expression is upregulated in colorectal cancer tissues and correlates with advanced tumor stage, poor prognosis, and altered tumor microenvironment composition. 6 In nasopharyngeal carcinoma, SDF4 secretion is stimulated by the LINC00173-RAB1B axis to promote tumor progression. 7 SDF4 protects against myocardial ischemia-reperfusion injury through the circPAN3/miR-29b-3p regulatory axis. 8 SDF4 serves as a reference gene in the Qliver methylation assay for hepatocellular carcinoma detection, achieving superior diagnostic performance compared to established biomarkers.