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25 sources retrieved · Most recent: April 2026 · Index updated 15 days ago
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PDIA4
protein disulfide isomerase family A member 4
Chromosome 7 · 7q36.1
NCBI Gene: 9601Ensembl: ENSG00000155660.11HGNC: HGNC:30167UniProt: A0A090N8Y2
208PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
RESEARCH IMPACT
Trending
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
RNA bindingendoplasmic reticulumcell surfaceprotein-disulfide reductase activityneurodegenerative diseaseovarian cancerneoplasmtriple-negative breast cancer
✦AI Summary

PDIA4 (protein disulfide isomerase family A member 4) is an endoplasmic reticulum-localized enzyme that catalyzes disulfide bond formation during protein folding 1. The protein functions as a protein disulfide isomerase with oxidoreductase activity through its active CXXC domains, playing a critical role in endoplasmic reticulum stress responses 2. PDIA4 expression is upregulated during ER stress through transcriptional regulation by XBP1, contributing to cellular survival under stress conditions 2. In cancer contexts, PDIA4 promotes tumor progression through multiple mechanisms: it confers resistance to ferroptosis by inducing the ATF4/SLC7A11 pathway in renal cell carcinoma 3, enhances angiogenesis by regulating VEGF-A secretion in glioblastoma 2, and supports cancer stem cell maintenance 4. The protein also modulates immune responses, with high expression correlating with reduced T cell infiltration and increased regulatory T cell presence 5. In metabolic contexts, PDIA4 contributes to insulin resistance and inflammation in skeletal muscle, with metformin alleviating these effects by modulating PDIA4 expression 6. Clinically, elevated PDIA4 expression is associated with poor prognosis across multiple cancer types and resistance to various therapies, making it a potential therapeutic target 75.

Sources cited
1
PDIA4 catalyzes disulfide bond formation during protein folding in the endoplasmic reticulum
PMID: 31794946
2
PDIA4 has oxidoreductase activity through CXXC domains and is upregulated by ER stress via XBP1 transcriptional regulation
PMID: 36997943
3
PDIA4 confers ferroptosis resistance via ATF4/SLC7A11 pathway in renal cell carcinoma
PMID: 36906674
4
PDIA4 supports cancer stem cell maintenance and immune evasion
PMID: 39542653
5
High PDIA4 expression correlates with reduced T cell infiltration and poor prognosis
PMID: 41185082
6
PDIA4 modulates insulin resistance and inflammation in skeletal muscle, with metformin effects mediated through PDIA4
PMID: 36619574
7
PDIA4 regulates unfolded protein response and is associated with poor survival in multiple myeloma
PMID: 41121130
Disease Associationsⓘ20
neurodegenerative diseaseOpen Targets
0.53Moderate
ovarian cancerOpen Targets
0.09Suggestive
neoplasmOpen Targets
0.09Suggestive
triple-negative breast cancerOpen Targets
0.09Suggestive
glioblastoma multiformeOpen Targets
0.09Suggestive
cancerOpen Targets
0.09Suggestive
gliomaOpen Targets
0.08Suggestive
diabetes mellitusOpen Targets
0.08Suggestive
alpha 1-antitrypsin deficiencyOpen Targets
0.08Suggestive
lung cancerOpen Targets
0.08Suggestive
renal cell carcinomaOpen Targets
0.08Suggestive
cervical cancerOpen Targets
0.08Suggestive
COVID-19Open Targets
0.08Suggestive
metabolic syndromeOpen Targets
0.07Suggestive
oral squamous cell carcinomaOpen Targets
0.07Suggestive
liver diseaseOpen Targets
0.06Suggestive
isolated asymptomatic elevation of creatine phosphokinaseOpen Targets
0.06Suggestive
nephrotic syndromeOpen Targets
0.06Suggestive
ovarian neoplasmOpen Targets
0.05Suggestive
pentosuriaOpen Targets
0.05Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
EDEM1Protein interaction99%GANABProtein interaction95%CRELD2Protein interaction94%UGGT1Protein interaction94%HSPA5Protein interaction93%PPIBProtein interaction93%
Tissue Expression6 tissues
Liver
100%
Ovary
21%
Lung
21%
Bone Marrow
18%
Heart
15%
Brain
13%
Gene Interaction Network
Click a node to explore
PDIA4EDEM1GANABCRELD2UGGT1HSPA5PPIB
PROTEIN STRUCTURE
Preparing viewer…
PDB3IDV · 1.95 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.67LoF Tolerant
pLIⓘ
0.00Tolerant
Observed/Expected LoF0.49 [0.37–0.67]
RankingsWhere PDIA4 stands among ~20K protein-coding genes
  • #2,012of 20,598
    Most Researched208 · top 10%
  • #4,895of 17,882
    Most Constrained (LOEUF)0.67
Genes detectedPDIA4
Sources retrieved25 papers
Response time—
📄 Sources
25▼
1
Construction and validation of a cuproptosis-related prognostic model for glioblastoma.
PMID: 36814929
Front Immunol · 2023
1.00
2
PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma.
PMID: 36906674
Cell Death Dis · 2023
0.90
3
Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.
PMID: 39865733
Brain · 2025
0.84
4
PDIA4: The basic characteristics, functions and its potential connection with cancer.
PMID: 31794946
Biomed Pharmacother · 2020
0.80
5
Downregulation of PDIA4 inhibits proliferation and migration in human oral squamous cell carcinoma.
PMID: 41185082
Hereditas · 2025
0.70