The gut incretin hormone glucose-dependent insulinotropic polypeptide (GIP) plays key roles in metabolic regulation. Evidence supports a beneficial role of GIP signaling on cardiometabolic health; however, effects of GIP on human cardiac progenitor cells (hCPC) are not known. This study investigates the ability of the saturated fatty acid palmitate to induce apoptosis, autophagy, and stress kinase activation in hCPC, and the potential effects of GIP on palmitate-induced abnormalities. hCPC expressed GIP receptor, at both mRNA and protein levels, evaluated by quantitative real-time PCR and immunoblotting, respectively. hCPC were treated with different doses (1-10-100 nM) of GIP for different times (up to 120 min), and exposure of hCPC to 10 nM GIP for 20 min induced both CREB (S133) and p44/p42 MAPK (T202/Y204) phosphorylation (p<0.05), assessed by immunoblotting. Co-treatment of hCPC with 10 nM GIP and 1µM GIP (3-30) NH2, a specific GIP receptor antagonist, for 20 min abrogated CREB (S133) phosphorylation, supporting GIP receptor engagement. Treatment of hCPC with 0.25 mM palmitate for 16 h induced c-Jun (S63), a downstream transcription factor of JNK 1/2, as well as p38 MAPK (T180/Y182) phosphorylation (evaluated by immunoblotting), autophagy (evaluated by immunoblotting for LC3II), and apoptosis (assessed by ELISA assay) (p<0.05). Pretreatment with 10 nM GIP for 1 h prevented palmitate-induced apoptosis (p<0.05), but not autophagy. Interestingly, palmitate effects on stress kinase activation were not prevented when hCPC were pretreated with GIP. These studies show for the first time that GIP has direct effects on hCPC through its receptor. GIP prevents palmitate-induced apoptosis, but not autophagy, through a signaling pathway independent of JNK 1/2 and p38 MAPK. Hence, GIP signaling might protect hCPC from lipotoxicity-induced metabolic abnormalities. Grant Acknowledgements: GenertionEU (PNRR, Age-it, n. PE0000015) and Fondazione Cianciola.