PALMD (palmdelphin) is a cytoskeletal regulator predominantly expressed in endothelial cells of cardiovascular tissues with critical roles in both cardiac and valvular function. 1 The protein exists as a cytosolic PALMD-KKVI splice variant that interacts with RANGAP1, regulating nucleocytoplasmic transport via the RAN-XPO1 pathway and affecting localization of transcriptional regulators p53 and p21. 1 Mechanically, PALMD enables formation of a protective perinuclear actin cap in endothelial cells exposed to flow stress, maintaining proper nuclear alignment. 1 In cardiac tissue, PALMD functions as a Z-disc-associated protein that stabilizes nexilin (NEXN), a critical component of junctional membrane complexes essential for calcium handling. 2 PALMD-deficient cardiomyocytes show compromised protection against isoproterenol-induced cardiac injury. 2 Disease relevance is substantial: reduced PALMD expression is a strong genetic risk factor for calcific aortic valve stenosis (CAVS), identified through genome-wide association studies. 3 Mechanistically, PALMD promotes CAVS pathogenesis through dual pathways—regulation of PFKFB3-mediated glycolysis and NF-κB-mediated inflammation in valve interstitial cells. 4 PALMD represents an AS-specific genetic risk locus distinct from coronary artery disease risk factors. 3 5 Outside cardiovascular contexts, PALMD shows anti-proliferative roles in breast cancer via PI3K/Akt pathway suppression. 6