P4HA1 encodes the alpha-1 subunit of prolyl 4-hydroxylase, an enzyme that catalyzes the post-translational hydroxylation of proline residues in collagen and other proteins, which is essential for collagen stability 1. The enzyme functions as part of an α2β2 tetramer in the endoplasmic reticulum, where it modifies -Xaa-Pro-Gly- sequences to form 4-hydroxyproline 1. Beyond its classical role in collagen synthesis, P4HA1 has emerged as a critical regulator in cancer biology through multiple mechanisms. In glioblastoma, P4HA1 increases succinate production, leading to enhanced succinylation of PGK1 and promoting aerobic glycolysis 2. P4HA1 also disrupts CD8+ T cell function by accumulating in mitochondria and altering the TCA cycle, promoting T cell exhaustion and immune escape 3. The gene is highly upregulated in various cancers including osteosarcoma and colorectal cancer, where it promotes tumor progression and serves as a negative prognostic factor 456. Targeting P4HA1 shows therapeutic promise, as its inhibition enhances anti-tumor immunity, increases sensitivity to cuproptosis inducers, and can be blocked by drugs like dextromethorphan to reduce fibrosis 357. These findings position P4HA1 as both a key metabolic regulator and potential therapeutic target in cancer treatment.