P3H3 (prolyl 3-hydroxylase 3) is a collagen-modifying enzyme that catalyzes hydroxylation of lysine residues in collagen alpha chains as part of a complex with PLOD1 and P3H4 1. P3H3 is particularly critical for lysine hydroxylation at collagen cross-linking sites in skin, bone, tendon, aorta, and cornea, though it appears to function redundantly with other prolyl 3-hydroxylases for prolyl 3-hydroxylation 2. Deficiency in P3H3 causes collagen lysine under-hydroxylation and abnormal cross-linking chemistry similar to Ehlers-Danlos syndrome type VIA 1. Beyond structural collagen biology, P3H3 functions as a tumor suppressor: its expression is downregulated in multiple cancer types through DNA methylation 34. In lung cancer, higher P3H3 expression correlates with lower tumor stage and grade, while ectopic expression inhibits cell proliferation, migration, and invasion while inducing apoptosis 4. In cervical cancer, P3H3 regulation by ZNF334 reverses epithelial-mesenchymal transition and enhances chemotherapy sensitivity 5. P3H3 also emerged as a diagnostic biomarker in dilated cardiomyopathy associated with cuproptosis pathways 6. Recent evidence suggests P3H3 activity can be modulated pharmacologically; dextromethorphan increases P3H3 thermal stability and activity, promoting collagen hyperhydroxylation and secretion inhibition to ameliorate lung fibrosis 7.