Syntaxin 4 (STX4) is a plasma membrane SNARE protein known to facilitate insulin granule exocytosis in pancreatic β-cells. Recent studies have uncovered that STX4 also exerts protective effects against inflammatory and metabolic stress by stabilizing mitochondrial function and suppressing NF-κB activation. In this project, we investigated the role of β-cell STX4 in modulating the secretome and paracrine signaling under pro-inflammatory conditions associated with β-cell senescence and type 1 diabetes.