GPLD1 (glycosylphosphatidylinositol specific phospholipase D1) is a liver-derived enzyme that cleaves glycosylphosphatidylinositol (GPI) anchors from membrane proteins, releasing them from cell surfaces 1. The enzyme functions as an 'exerkine,' with plasma concentrations increasing after exercise and correlating with improved cognitive function in aged mice and active elderly humans 1. GPLD1 operates through a liver-to-brain axis, where it targets brain vasculature by cleaving GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP), thereby improving blood-brain transport and reversing age-related memory deficits 2. In cardiac tissue, GPLD1 localizes to plasma and mitochondrial membranes via phosphatidylinositol 4,5-bisphosphate, where it cleaves uPAR (urokinase-type plasminogen activator receptor) to maintain calcium homeostasis and mitochondrial function, providing cardioprotective effects against heart failure 3. The enzyme also plays a role in cancer, where GPLD1+ cells represent slowly cycling cancer stem cells contributing to chemotherapy resistance, and GPLD1 promotes epithelial-mesenchymal transition by cleaving PRSS8 and activating Wnt signaling 4. GPLD1 is primarily expressed in liver with circulating concentrations of 5-10 µg/mL 5.