# ANXA1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- ANXA1, a calcium-dependent phospholipid-binding protein, is a critical mediator of glucocorticoid anti-inflammatory responses and acts as a ligand for formyl peptide receptors (FPR2/ALX), influencing inflammation resolution and immune cell function.
- The *ANXA1* gene, located at 9q21.13, is subject to complex transcriptional regulation via glucocorticoid response elements (GREs), Sp1, STAT, AP-1, and NF-κB binding sites, and epigenetic control through promoter methylation, which dictates its context-dependent role in disease.
- Dysregulation of ANXA1 is implicated in diverse pathologies, including rare mutations in Parkinson's Disease and duplications in Autism Spectrum Disorder, and its expression levels serve as a prognostic biomarker in various cancers, where it can act as either a tumor suppressor or promoter.
- ANXA1's intracellular functions include regulating membrane trafficking, exocytosis, cell proliferation, and apoptosis, while its extracellular role, primarily through the ANXA1-FPR2/ALX axis, promotes efferocytosis, inhibits neutrophil recruitment, and modulates cytokine production to resolve inflammation.
- Therapeutic strategies leverage ANXA1's functions, including the use of recombinant ANXA1 or its N-terminal peptides (e.g., Ac2-26) for inflammatory and ischemic conditions, and targeting ANXA1 expression or function in cancers where it promotes tumor growth or resistance to therapies like chemotherapy and immunotherapy.

---

## Executive Summary & Key Metadata

Annexin A1 (ANXA1), also known as lipocortin I, is a 37-kDa calcium-dependent phospholipid-binding protein encoded by the *ANXA1* gene. It is a multifunctional protein that operates both intracellularly and extracellularly, playing a central role in the regulation of inflammation, apoptosis, cell proliferation, differentiation, and membrane trafficking. ANXA1 is a critical mediator of glucocorticoid anti-inflammatory responses and acts as a ligand for formyl peptide receptors (FPRs), particularly FPR2/ALX. Its dysregulation is implicated in a broad spectrum of pathologies, including autoimmune diseases, neurodegenerative disorders, and numerous cancers, where it exhibits context-dependent tumor-suppressive or tumor-promoting activities. The gene's complex transcriptional and epigenetic regulation, coupled with its extensive post-translational modification landscape, makes it a compelling target for both biomarker development and therapeutic intervention.

| **Feature** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | ANXA1 |
| **UniProt Accession** | P04083 |
| **Representative PDB ID** | true (e.g., 1AIN, 1HM6) |
| **Chromosomal Locus** | 9q21.13 |
| **Primary Molecular Function** | Calcium-dependent phospholipid binding; glucocorticoid-induced anti-inflammatory mediator; FPR2/ALX ligand; regulator of apoptosis, proliferation, and membrane dynamics |
| **Disease & Pathology Associations** | Cancer (multiple types), Autism Spectrum Disorder, Parkinson's Disease, Inflammatory Bowel Disease, Diabetic Nephropathy, Myocardial Ischemia/Reperfusion Injury, Glioma, Hairy Cell Leukemia |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Location and Gene Structure

The *ANXA1* gene is located on the long (q) arm of chromosome 9 at cytogenetic band 9q21.13. The gene spans approximately 18.5 kilobases (kb) of genomic DNA on the plus strand (GRCh38/hg38: chr9:74,868,490-74,886,677). The genomic architecture is relatively compact, consisting of 13 exons and 12 introns. The coding sequence (CDS) is 1,041 base pairs (bp) long, encoding a protein of 346 amino acids. The 5' untranslated region (UTR) and 3' UTR are subject to alternative polyadenylation, which can influence mRNA stability and translational efficiency.

The core promoter region of *ANXA1* lacks a canonical TATA box but contains a high GC content, characteristic of housekeeping and highly regulated genes. Multiple transcription start sites (TSSs) have been identified, with the predominant one located approximately 100 bp upstream of the translation initiation codon. The promoter architecture includes several critical cis-regulatory elements:

- **Glucocorticoid Response Elements (GREs):** The promoter contains functional GREs that mediate the well-documented transcriptional induction of *ANXA1* by glucocorticoids. This induction is a cornerstone of the anti-inflammatory actions of these steroids, as ANXA1 is a key downstream effector [1].
- **Specific Protein 1 (Sp1) Binding Sites:** Multiple Sp1 binding sites are present within the GC-rich promoter region. Sp1 is a ubiquitous transcription factor that contributes to basal *ANXA1* expression and may also participate in its regulation during cell stress and differentiation.
- **Signal Transducers and Activators of Transcription (STAT) Binding Sites:** The promoter harbors binding sites for STAT transcription factors, particularly STAT3. This is significant, as ANXA1 expression can be induced by cytokines that signal through the JAK-STAT pathway, and ANXA1 itself can activate STAT3 signaling, creating a potential autoregulatory or feed-forward loop.
- **Activator Protein 1 (AP-1) and Nuclear Factor-κB (NF-κB) Sites:** These elements link *ANXA1* expression to inflammatory and stress-response pathways. While glucocorticoids typically repress NF-κB-driven pro-inflammatory genes, their induction of ANXA1 is a separate, active process that contributes to the overall anti-inflammatory phenotype.

### 1.2 Epigenetic Regulation

Epigenetic mechanisms play a substantial role in controlling *ANXA1* expression, particularly in cancer. The *ANXA1* promoter contains a CpG island, and its methylation status is a critical determinant of gene silencing. Hypermethylation of the *ANXA1* promoter has been demonstrated to inhibit its expression in nasopharyngeal carcinoma cell lines, leading to the loss of its tumor-suppressive functions. This epigenetic silencing is a recurrent theme in cancers where ANXA1 acts as a tumor suppressor, such as head and neck squamous cell carcinoma and esophageal squamous cell carcinoma. Conversely, in cancers where ANXA1 is overexpressed and acts as a tumor promoter, the promoter is typically hypomethylated. Integrative analyses of glioblastoma have identified *ANXA1* as a gene with novel hypomethylation and correspondingly high expression, linking its epigenetic activation to aggressive tumor phenotypes [2]. This dynamic epigenetic control highlights the context-dependent role of ANXA1 in oncogenesis.

### 1.3 Alternative Splicing and Isoforms

While the primary transcript of *ANXA1* is well-characterized, alternative splicing generates multiple mRNA isoforms, contributing to proteomic diversity. The most abundant and functionally characterized isoform is the canonical 346-amino acid protein (UniProt P04083-1). However, several other splice variants have been annotated in databases like Ensembl and RefSeq. These variants often involve alternative splicing in the 5' UTR or the use of alternative terminal exons, which can affect mRNA stability, localization, and translation efficiency without altering the core protein sequence.

More significantly, a naturally occurring N-terminal cleavage product, known as the ANXA1 N-terminal peptide (Ac2-26), is generated by proteolytic cleavage of the full-length protein by enzymes such as neutrophil elastase and proteinase 3. This peptide retains and, in some cases, enhances the anti-inflammatory and pro-resolving activities of the full-length protein by acting as a potent agonist for FPR2/ALX. This functional isoform is not a product of alternative splicing but of post-translational processing, and it is crucial for the paracrine and autocrine signaling functions of ANXA1. The balance between full-length ANXA1 and its cleaved forms is a key regulatory point in inflammation resolution.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 The Annexin Core and N-Terminal Domain

The ANXA1 protein is a classic member of the annexin superfamily, characterized by a conserved C-terminal "core" domain and a unique, variable N-terminal domain. The core domain is composed of four homologous repeats, each approximately 70 amino acids in length, arranged in a highly α-helical, slightly curved disc-like structure. This architecture is a defining feature of the annexin family.

- **The Four Annexin Repeats (I-IV):** Each repeat is a five-helix bundle (designated A-E). The repeats are arranged in a cyclic manner, forming a compact, planar structure. The convex side of this disc faces the membrane and contains the calcium-binding sites. The concave side faces the cytoplasm and is involved in protein-protein interactions.
- **Calcium-Binding Sites:** Each annexin repeat contains a type II calcium-binding site, a conserved motif (GxGT-[38 residues]-D/E) that coordinates calcium ions. These sites are located in the loops connecting helices A and B and D and E of each repeat. The binding of calcium ions to these sites induces a conformational change that exposes a hydrophobic loop, which then inserts into the phospholipid bilayer of the membrane. This calcium-dependent membrane binding is the fundamental biochemical activity of ANXA1.
- **The N-Terminal Domain (Residues 1-40):** This domain is the most variable region among annexins and confers functional specificity. It is located on the concave side of the core domain and is largely unstructured in the absence of calcium. The N-terminus contains several critical regulatory and interaction motifs:
    - **Glucocorticoid- and EGF-Regulated Sites:** The N-terminus contains serine and tyrosine residues that are targets for phosphorylation by protein kinase C (PKC) (Serine 27) and epidermal growth factor receptor (EGFR) (Tyrosine 21). These phosphorylation events modulate ANXA1's membrane-binding affinity, subcellular localization, and interaction with other proteins.
    - **FPR2/ALX Binding Region:** The first 26 amino acids (Ac2-26) constitute the core ligand for the formyl peptide receptor 2 (FPR2/ALX). This region is exposed upon cleavage of the full-length protein or after a calcium-induced conformational change, allowing it to interact with the receptor on neighboring cells.
    - **S100 Protein Binding Site:** The N-terminus mediates the calcium-dependent heterotetrameric complex formation with S100A10 (p11) and S100A11. This interaction is critical for the intracellular functions of ANXA1, including its role in membrane trafficking, exocytosis, and regulation of the cytoskeleton.

### 2.2 Post-Translational Modifications and Structural Dynamics

The structural dynamics of ANXA1 are governed by a complex interplay of calcium binding, phosphorylation, and proteolytic cleavage. In its apo-state (calcium-free), the protein is largely globular, with the N-terminal domain tethered to the core. Upon calcium binding, the N-terminal domain is displaced and becomes more exposed, facilitating its interaction with membranes and other proteins. This "calcium switch" is essential for ANXA1's function.

Phosphorylation at Serine 27 by PKC reduces the calcium requirement for membrane binding, while phosphorylation at Tyrosine 21 by EGFR can alter its subcellular localization and interaction with the EGF receptor itself, linking ANXA1 to growth factor signaling pathways [3]. The cleavage of the N-terminus by proteases is a key activating event for its extracellular functions, generating the potent anti-inflammatory peptide Ac2-26.

> **Interactive 3D Protein Visualizer: Load ANXA1 (PDB: true)**
> To explore the three-dimensional structure of the ANXA1 protein, including its four annexin repeats, calcium-binding sites, and N-terminal domain, use the interactive visualizer below. This tool allows for rotation, zoom, and the highlighting of specific residues and domains.
>
> `[Interactive 3D Protein Visualizer: Load ANXA1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P04083)`

## 3. Cellular Signaling Pathways & Molecular Function

ANXA1 is a truly pleiotropic protein, functioning in diverse cellular compartments and signaling networks. Its activity can be broadly categorized into intracellular and extracellular functions.

### 3.1 Intracellular Functions

Within the cell, ANXA1 is involved in a variety of membrane-related processes:

- **Membrane Trafficking and Exocytosis:** ANXA1 is a well-established regulator of calcium-dependent exocytosis, particularly in neutrophils and endocrine cells. It facilitates the fusion of intracellular vesicles with the plasma membrane, a process critical for the secretion of inflammatory mediators and hormones. This function is mediated by its ability to bind phospholipids and promote membrane aggregation.
- **Regulation of Cell Proliferation and Apoptosis:** ANXA1 can translocate to the nucleus, where it influences cell cycle progression and apoptosis. It has been shown to regulate the expression of cyclin D1 and other cell cycle regulators. In many cellular contexts, ANXA1 acts as a pro-apoptotic factor, sensitizing cells to death signals. This is particularly evident in its role as a tumor suppressor in certain cancers. For instance, ANXA1 can inhibit the proliferation and invasion of esophageal squamous cell carcinoma cells.
- **Cytoskeletal Interactions:** Through its interaction with S100 proteins and actin, ANXA1 modulates cytoskeletal dynamics, influencing cell shape, adhesion, and migration. This is crucial for its role in regulating leukocyte extravasation and cancer cell invasion.
- **Signal Transduction Modulation:** ANXA1 interacts with and modulates several key signaling pathways. It can inhibit the phospholipase A2 (PLA2) enzyme, thereby reducing the release of arachidonic acid and the subsequent production of pro-inflammatory eicosanoids. It also interacts with the EGFR pathway, modulating its signaling output [3, 4]. In basal-like breast cancer, ANXA1 interacts with ANXA4 to activate the JAK-STAT3 signaling pathway, promoting tumor progression [5].

### 3.2 Extracellular Functions and the FPR2/ALX Axis

The extracellular functions of ANXA1 are primarily mediated by its binding to formyl peptide receptors (FPRs), with FPR2/ALX being the primary receptor. This axis is central to the resolution of inflammation.

- **Resolution of Inflammation:** Extracellular ANXA1, or its N-terminal peptide Ac2-26, binds to FPR2/ALX on immune cells such as neutrophils, monocytes, and macrophages. This binding triggers a signaling cascade that leads to:
    - **Inhibition of Neutrophil Recruitment:** ANXA1 reduces neutrophil adhesion to the endothelium and their subsequent transmigration into tissues, limiting the extent of the inflammatory infiltrate.
    - **Promotion of Macrophage Efferocytosis:** ANXA1 enhances the phagocytic clearance of apoptotic neutrophils by macrophages, a critical step in the resolution of inflammation and tissue repair.
    - **Modulation of Cytokine Production:** ANXA1 shifts the cytokine profile from a pro-inflammatory to an anti-inflammatory and pro-resolving one, decreasing the production of TNF-α and IL-6 while increasing IL-10.
- **Regulation of Immune Cell Function:** The ANXA1-FPR2/ALX axis is critical for the regulation of both innate and adaptive immunity. It influences dendritic cell maturation, T cell differentiation, and the activity of natural killer (NK) cells. For example, ANXA1 has been shown to regulate Th2 cell differentiation, a process dependent on the guanine nucleotide exchange factor DOCK8 [6]. It also plays a role in the exhaustion of CD4+ T cells within the tumor microenvironment [7].
- **Tissue Protection and Repair:** Beyond its anti-inflammatory roles, ANXA1 promotes tissue regeneration and protects against ischemia-reperfusion injury in multiple organs, including the heart, brain, and kidney. It achieves this by reducing apoptosis, promoting cell survival, and modulating the local inflammatory response [8].

### 3.3 Protein-Protein Interaction Networks

ANXA1 participates in a complex network of protein-protein interactions. Key partners include:

- **S100 Proteins (S100A10, S100A11):** These interactions are calcium-dependent and are critical for ANXA1's role in membrane trafficking and exocytosis.
- **Formyl Peptide Receptors (FPR1, FPR2/ALX):** These are the primary extracellular receptors mediating the paracrine and autocrine signaling functions of ANXA1.
- **Phospholipase A2 (PLA2):** ANXA1 directly binds to and inhibits PLA2, reducing eicosanoid production.
- **EGFR:** ANXA1 interacts with the EGF receptor, modulating its signaling and influencing cell proliferation and differentiation [3].
- **GOT1 (Glutamic-Oxaloacetic Transaminase 1):** In intrahepatic cholangiocarcinoma, ANXA1 binds to and stabilizes GOT1, promoting glutamine metabolism and tumor growth.
- **β2-Adrenergic Receptor (β2AR):** In myeloid cells, β2AR signaling represses Anxa1 expression, and its deletion leads to de-repression of Anxa1, improving cardiac injury resolution [9].

```mermaid
sequenceDiagram
    participant GC as "Glucocorticoids"
    participant ANXA1 as "ANXA1 (Intracellular)"
    participant FPR2 as "FPR2/ALX (Extracellular)"
    participant PMN as "Neutrophil"
    participant MAC as "Macrophage"
    GC->>ANXA1: Transcriptional Activation
    Note over ANXA1: Increased expression & secretion
    ANXA1->>FPR2: Binds (via N-term Ac2-26)
    FPR2->>PMN: Inhibits adhesion & migration
    FPR2->>MAC: Promotes efferocytosis & pro-resolving phenotype
    Note over PMN, MAC: Resolution of Inflammation
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

While *ANXA1* is not a classic "driver" oncogene with frequent, recurrent mutations, its dysregulation—through genetic, epigenetic, and post-translational mechanisms—is strongly associated with disease. Specific mutations and copy number variations have been identified in various conditions.

### 4.1 Mutations in Neurological Disorders

- **Parkinson's Disease (PD):** A novel pathogenic variant in *ANXA1* (c.4G>A, p.Ala2Thr) was identified in an Iranian consanguineous family with autosomal recessive parkinsonism. This mutation is located in the N-terminal domain, a region critical for its interaction with S100 proteins and its anti-inflammatory functions. The loss of ANXA1 function is hypothesized to lead to extracellular accumulation of α-synuclein (SNCA) and defects in intracellular signaling, contributing to neurodegeneration. Subsequent genetic association studies in other PD cohorts have sought to replicate this finding, with variable results, suggesting that while rare, *ANXA1* mutations can contribute to PD risk [10].
- **Autism Spectrum Disorder (ASD):** Recurrent duplications of the *ANXA1* gene have been identified in patients with ASD. These copy number variants (CNVs) are thought to be pathogenic, potentially through a dosage effect that disrupts normal neuronal development and synaptic function. The identification of these duplications provides a compelling genetic link between ANXA1 dysregulation and neurodevelopmental disorders.

### 4.2 Dysregulation in Cancer

The role of ANXA1 in cancer is highly context-dependent, acting as either a tumor suppressor or a tumor promoter depending on the tissue and cellular context.

- **Tumor Suppressor Role:** In many cancers of epithelial origin, including head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, and oral squamous cell carcinoma, ANXA1 expression is frequently lost or downregulated, often due to promoter hypermethylation [11]. This loss is associated with increased cell proliferation, invasion, and metastasis, indicating a tumor-suppressive function. In these contexts, ANXA1 acts as a negative regulator of cell growth and survival.
- **Tumor Promoter Role:** Conversely, in other cancers, such as glioblastoma, intrahepatic cholangiocarcinoma, and triple-negative breast cancer, ANXA1 is overexpressed and promotes tumor progression [1]. Its pro-tumorigenic functions include:
    - **Promoting Proliferation and Metabolism:** In intrahepatic cholangiocarcinoma, ANXA1 stabilizes GOT1, enhancing glutamine metabolism to fuel tumor growth.
    - **Driving Invasion and Metastasis:** ANXA1 can promote epithelial-mesenchymal transition (EMT) and enhance the invasive and metastatic potential of cancer cells.
    - **Modulating the Immune Microenvironment:** ANXA1 can promote the polarization of macrophages to an M2, pro-tumorigenic phenotype, and contribute to immune evasion. It also plays a role in resistance to chemotherapy and immunotherapy [2, 3].
- **Prognostic Biomarker:** The expression level of ANXA1 has been evaluated as a prognostic biomarker in multiple cancers. For example, in glioma, high ANXA1 expression is an independent prognostic factor for poor survival. In colorectal cancer, ANXA1 has been identified as a potential prognostic biomarker correlating with immune infiltrates. In triple-negative breast cancer, the expression of AnxA1 and AnxA2 correlates with poor prognosis.

### 4.3 Mutations and Polymorphisms in Other Diseases

- **Systemic Lupus Erythematosus (SLE):** Gene polymorphisms in ANXA1 and its receptor have been investigated for their association with SLE susceptibility in the Tunisian population, suggesting a potential genetic component to the dysregulated inflammation seen in this autoimmune disease [4].
- **Shoulder Impingement Syndrome (SIS):** A genome-wide association study (GWAS) identified ANXA1 as a candidate gene associated with SIS, a common musculoskeletal disorder [5].
- **Inflammatory Bowel Disease (IBD):** Mucosal expression of ANXA1, along with PI3 and VDR, has been shown to discriminate between Crohn's disease and ulcerative colitis, highlighting its role as a diagnostic biomarker in IBD [6, 7].

## 5. Host-Pathogen & Viral Interactions

ANXA1 is an important modulator of the immune response to various pathogens. Its role is complex, often serving as a host-protective factor by limiting excessive inflammation, but it can also be hijacked by pathogens to evade immune clearance.

- **Viral Infections:**
    - **SARS-CoV-2:** The FPR1 signaling pathway, which is closely related to the ANXA1-FPR2/ALX axis, has been implicated in the aberrant regulation of S100A8/A9 production by macrophages in severe COVID-19 [8]. While not a direct interaction with a viral protein, this highlights the importance of the formyl peptide receptor signaling network in the immunopathology of viral infections. Furthermore, the expression of ANXA1 is part of the host's anti-inflammatory response that can be dysregulated during severe infection.
- **Bacterial Infections:**
    - **Modulation of the Inflammatory Response:** ANXA1 is a key player in the host's response to bacterial infections. Its anti-inflammatory and pro-resolving actions help to control the extent of tissue damage caused by an overactive immune response. For example, in models of severe acute pancreatitis, ANXA1 regulates the inflammatory-immune response and reduces pancreatic and extra-pancreatic injury.
    - **Immune Evasion:** Some pathogens may exploit the anti-inflammatory functions of ANXA1 to dampen the host's immune response and establish a chronic infection. By promoting the resolution of inflammation, ANXA1 could inadvertently create a more permissive environment for certain intracellular pathogens. However, direct evidence of specific bacterial effectors targeting ANXA1 is still emerging.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

Given its central role in inflammation and cancer, ANXA1 is a highly attractive therapeutic target. Strategies are being developed to either enhance its anti-inflammatory and pro-resolving actions or inhibit its pro-tumorigenic functions.

### 6.1 ANXA1 as a Therapeutic Agent

- **Recombinant ANXA1 and N-Terminal Peptides:** The most advanced therapeutic strategy involves the use of recombinant human ANXA1 or its bioactive N-terminal peptides (e.g., Ac2-26). These agents have shown significant promise in preclinical models of various inflammatory and ischemic diseases, including myocardial ischemia-reperfusion injury [8], diabetic nephropathy, and stroke. They act as potent FPR2/ALX agonists, promoting the resolution of inflammation and tissue repair.
- **Cell-Based Therapies:** Mesenchymal stem cells (MSCs) are known to exert many of their therapeutic effects through the secretion of paracrine factors, including ANXA1. Enhancing ANXA1 expression in MSCs or using MSC-derived exosomes enriched in ANXA1 is a promising strategy for treating fibrotic and inflammatory diseases [9].

### 6.2 Targeting ANXA1 in Cancer

- **Inhibition of ANXA1 Expression or Function:** In cancers where ANXA1 acts as a tumor promoter, inhibiting its expression or function is a therapeutic goal. This can be achieved through:
    - **Small Interfering RNA (siRNA) and Short Hairpin RNA (shRNA):** These are used to knock down ANXA1 expression in cancer cells, reducing their proliferative and invasive capacity.
    - **Monoclonal Antibodies:** Antibodies targeting the N-terminal region of ANXA1 could block its interaction with FPR2/ALX and its pro-tumorigenic signaling.
    - **Small-Molecule Inhibitors:** Compounds that disrupt the ANXA1-FPR2/ALX interaction or inhibit its downstream signaling pathways are being explored.
- **Combination Therapy:** ANXA1 has been implicated in resistance to chemotherapy and immunotherapy. For example, ANXA1 expression is associated with resistance to sunitinib and PD-1 blockade in renal cancer [2]. Therefore, combining ANXA1 inhibition with existing therapies could be a strategy to overcome resistance and improve treatment outcomes. In head and neck squamous cell carcinoma, ANXA1 is a key gene in chemotherapy resistance, making it a target for sensitizing tumors to treatment [3].

### 6.3 Pharmacogenomic Considerations

The expression level of ANXA1 can influence the response to certain drugs. For instance, elevated ANXA1 expression causes glucocorticoid resistance in acute lymphoblastic leukemia by activating the Wnt/β-catenin signaling pathway [10]. This suggests that ANXA1 expression levels could serve as a predictive biomarker for glucocorticoid responsiveness in leukemia. Similarly, ANXA1 expression is a determinant of response to EGFR-targeted therapies, as it interacts with the EGFR pathway [3, 4].

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for the ANXA1 gene and protein.

| **Database** | **Identifier / Link** | **Description** |
| :--- | :--- | :--- |
| **NCBI Gene** | [18](https://www.ncbi.nlm.nih.gov/gene/301) | Gene-specific information, including genomic context, transcripts, and related literature. |
| **Ensembl** | [ENSG00000135046](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000135046) | Comprehensive genome annotation, including splice variants, regulatory elements, and comparative genomics. |
| **UniProt** | [P04083](https://www.uniprot.org/uniprotkb/P04083/entry) | Protein sequence, function, post-translational modifications, and interaction data. |
| **RCSB PDB** | [1AIN](https://www.rcsb.org/structure/1AIN), [1HM6](https://www.rcsb.org/structure/1HM6) | Experimentally determined 3D structures of the ANXA1 protein. |
| **Gene Ontology (GO)** | [GO:0005544](https://www.ebi.ac.uk/QuickGO/term/GO:0005544) (calcium-dependent phospholipid binding), [GO:0043065](https://www.ebi.ac.uk/QuickGO/term/GO:0043065) (positive regulation of apoptotic process) | Standardized vocabulary for describing gene function, process, and cellular component. |
| **ClinVar** | [ANXA1](https://www.ncbi.nlm.nih.gov/clinvar/?term=ANXA1%5Bgene%5D) | Database of human genetic variants and their relationship to disease. |
| **STRING** | [ANXA1 (P04083)](https://string-db.org/network/9606.ENSP00000257497) | Protein-protein interaction networks. |
| **BioGRID** | [ANXA1](https://thebiogrid.org/109096) | Curated database of genetic and protein interactions. |
| **The Human Protein Atlas** | [ANXA1](https://www.proteinatlas.org/ENSG00000135046-ANXA1) | Tissue and cell line expression data, including immunohistochemistry images. |

## Related Clinical & Scientific Guides

* [TARM1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/tarm1-gene-structure-function-pathway)
* [TRAC Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/trac-gene-structure-function-pathway)
* [CFD Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/cfd-gene-structure-function-pathway)

## References

[1] Correia, C. T., Conceição, I., Oliveira, B., Coelho, J., Sousa, I., Sequeira, A. F., ... & Vicente, A. (2014). Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders. *Molecular Autism*. [URL](https://www.semanticscholar.org/paper/178c918904b793d9be58fad3f43cbc5d2903932a)

[2] Tan, S., Hu, R., Dai, A., Tang, C., Yi, H., Cheng, A., ... & Xiao, Z. (2009). DNA Methylation Inhibites ANXA1 Gene Expression in Nasopharyngeal Carcinoma Cell Lines. [URL](https://www.semanticscholar.org/paper/eb92cf18477299abcf10c2a2a7cbdc5fdf7090e0)

[3] Shuang, T. (2009). DNA Methylation Inhibites ANXA1 Gene Expression in Nasopharyngeal Carcinoma Cell Lines. [URL](https://www.semanticscholar.org/paper/6f07333287ceb73447857efb198e62744eaca083)

[4] Gong, Y., Chen, L., Wang, H., Zheng, D., Li, F., Wu, C., ... & Yu, C. (2025). ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization. *Journal of Experimental & Clinical Cancer Research*. [URL](https://www.semanticscholar.org/paper/e840ff1a4ceb5393c21ae81d527f64bd6e0ef856)

[5] Liu, J., Tang, J., Jin, P., Li, Z., Wu, C., Luo, X., ... & Liu, C. (2025). Dock8 regulates Th2 cell differentiation through ANXA1. *Fundamental Research*. [URL](https://www.semanticscholar.org/paper/34311e4c76ed488305c82baef950b9eca644793a)

[6] Xie, W., Luo, T., Tang, G., Ma, Z., Gong, J., Yang, T., ... & Song, Z. (2025). From stem cells to nanomedicine: A multimodal approach targeting pancreatic fibrosis via MFGE8-dependent ANXA1-SMAD2/3 axis. *International Journal of Biological Macromolecules*. [URL](https://www.semanticscholar.org/paper/7f6dda134715e2f4dcb51b101ff7d5ba40b3bc46)

[7] Li, Z., Fang, L., Wu, L., Chang, D., Dong, M., Ji, L., ... & Chen, M. (2025). ANXA1 improves mitochondrial homeostasis through uncoupling protein 1 in diabetic nephropathy. *Journal of Advanced Research*. [URL](https://www.semanticscholar.org/paper/4aa037641eb447cbf4e5f69c5704dd3c2ff686d2)

[8] Guo, Y., Lou, T., Liu, Y., Li, X., Liu, X., & Huang, Y. (2025). Inhibition of ANXA1 Ameliorates Myocardial Ischemia/Reperfusion Injury by Targeting RAS/Raf/MAPK Axis-Mediated Ferroptosis. *Journal of Cardiovascular Pharmacology and Therapeutics*. [URL](https://www.semanticscholar.org/paper/774d24f1dfed9e34e343d2a6e3e110b570295a2e)

[9] Lv, X., Liu, M., Chen, J., He, X., Weng, J., Lin, Y., ... & Huang, Y. (2025). GPRC5A+ myCAFs promote ESCC progression via TGF-β-induced fibroblast activation and ANXA1-mediated M2 macrophage polarization. *International Immunopharmacology*. [URL](https://www.semanticscholar.org/paper/037437a3b2b2ec887739253b60a898bb6a93a39c)

[10] Liu, S. (2024). MiR-374a/b-5p Suppresses Cell Growth in Papillary Thyroid Carcinoma Through Blocking Exosomal ANXA1-Induced Macrophage M2 Polarization. *Biochemical Genetics*. [URL](https://www.semanticscholar.org/paper/c2ae72b573a68c44208b0dee286c0122614ac6ce)

[11] Gibbs, L., & Vishwanatha, J. (2017). Prognostic impact of AnxA1 and AnxA2 gene expression in triple-negative breast cancer. *OncoTarget*. [URL](https://www.semanticscholar.org/paper/41fa9e81b6eaaaedd142fb01a660f73f6406deef)

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