P4HB (prolyl 4-hydroxylase subunit beta) is a multifunctional endoplasmic reticulum (ER) protein that catalyzes formation, breakage, and rearrangement of disulfide bonds through two thioredoxin domains 1. As the β-subunit of collagen prolyl 4-hydroxylase, P4HB is essential for collagen hydroxylation and triple helix stability, with expression regulated by cytokines, transcription factors, and microRNAs 2. At the cell surface, P4HB functions as a reductase cleaving disulfide bonds of exofacial proteins, while intracellularly it forms and rearranges disulfide bonds of nascent proteins 1. P4HB also acts as a chaperone—at high concentrations following phosphorylation, it inhibits protein misfolding aggregation; at low concentrations, it facilitates aggregation 3. Structurally, P4HB comprises part of multichaperone condensates that enhance ER protein folding 3. Clinically, P4HB dysregulation associates with multiple malignancies. Meta-analysis of 4121 cancer patients revealed that elevated P4HB expression correlates with significantly shorter overall survival (HR 1.90; 95% CI 1.50-2.40) and is upregulated in 13 cancer types 4. P4HB participates in cancer progression through HIF-1α-regulated pathways in gastric cancer 5 and represents part of prognostic signatures in pancreatic cancer liver metastasis 6. In hepatic fibrosis, the IRE1/P4HB axis regulates collagen production and disease severity 7. Additionally, P4HB mutations cause Cole-Carpenter syndrome, with P4HB mutations identified in 0.6% of moderate-to-severe osteogenesis imperfecta cases 8, highlighting its critical role in collagen maturation and bone homeostasis.