P4HA3 (prolyl 4-hydroxylase subunit alpha 3) is a catalytic subunit of collagen prolyl 4-hydroxylase that catalyzes post-translational hydroxylation of proline residues in collagen's -Xaa-Pro-Gly- sequences, essential for collagen triple helix stability 1. This enzymatic activity occurs in the endoplasmic reticulum lumen as part of procollagen processing. Beyond its canonical collagen synthesis function, P4HA3 has emerged as a significant oncogenic regulator across multiple cancer types. In colorectal cancer, P4HA3 suppresses ferroptosis by stabilizing ACSL4 mRNA through downregulation of the RNA-binding protein AUF1, promoting tumor growth 2. In head and neck squamous cell carcinoma, P4HA3 promotes progression via epithelial-mesenchymal transition (EMT) and WNT/β-catenin pathway activation 3. In melanoma, P4HA3 overexpression increases proliferation and invasiveness, with high expression correlating with poor prognosis 4. Similarly, in gastric cancer, P4HA3 is epigenetically activated by Slug and associated with enhanced metastasis and poor survival 5. A pan-cancer analysis revealed P4HA3 expression correlates with tumor microenvironment immune cell infiltration, proliferation markers, and EMT markers, with P4HA3 deficiency promoting anti-tumor immunotherapy response 6. In non-malignant diseases, P4HA3 participates in pathological fibrosis. In systemic sclerosis, TGF-β1 upregulates P4HA3 to promote collagen synthesis in fibroblasts, and C-P4H inhibition ameliorates experimental fibrosis 7. These findings establish P4HA3 as a promising therapeutic target across cancer and fibrotic diseases.