PXDNL (peroxidasin-like) is a cardiac-enriched protein that has evolutionarily lost peroxidase enzymatic activity while retaining structural homology to peroxidasin 1. In the heart, PXDNL localizes to cardiomyocyte cell-cell junctions and antagonizes PXDN-mediated peroxidase function, which regulates extracellular matrix (ECM) collagen cross-linking 1. Elevated PXDNL expression in failing myocardium suggests a role in pathological ECM remodeling 1. Beyond cardiac tissue, PXDNL exhibits oncogenic properties in multiple cancers. In breast cancer, high PXDNL expression independently predicts poor overall and relapse-free survival 2. Similarly, in urothelial bladder carcinoma, PXDNL promotes cell motility through the Wnt/β-catenin pathway and epithelial-to-mesenchymal transition (EMT), serving as an independent prognostic factor 3. PXDNL functions as a risk factor in TME-related prognostic signatures, correlating with immunosuppressive microenvironments and reduced immunotherapy response 45. Genetically, PXDNL variants associate with complex diseases: a gastroparesis risk allele correlates with increased abdominal pain severity and gastric muscularis PXDNL expression 6, while plasma PXDNL shows causal associations with cluster headache and interacts with both acute and preventive drug targets 7. Human knockouts reveal PXDNL loss-of-function phenotypes distinct from GWAS-associated traits 8.