# LGALS3 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The *LGALS3* gene encodes galectin-3 (Gal-3), a pleiotropic β-galactoside-binding lectin with a unique chimeric structure, playing roles in cell adhesion, proliferation, apoptosis, inflammation, and fibrosis.
- Galectin-3 exhibits context-dependent intracellular and extracellular functions, including anti-apoptotic signaling via mitochondrial stabilization and JNK inhibition, and extracellular roles in cell adhesion, immune modulation (e.g., M2 macrophage polarization), and potent pro-fibrotic activity through TGF-β/Smad signaling.
- Dysregulation of *LGALS3* is implicated in a broad spectrum of pathologies, including cancer (pancreatic, glioblastoma), heart failure, chronic kidney disease, autoimmune disorders, and neurodegenerative diseases, with specific SNPs like rs4644 and rs4652 associated with susceptibility and outcomes in conditions such as sickle cell anemia and rheumatoid arthritis.
- *LGALS3* expression is tightly regulated by a TATA-less, GC-rich promoter with binding sites for Sp1, AP-1, NF-κB, and C/EBP, and its induction can be mediated by chromatin remodelers like BRG1 in response to injury, while repressors like KLF3 maintain low basal expression.
- Galectin-3 is involved in host-pathogen interactions, notably defending against bacterial infections like *Pseudomonas aeruginosa* by enhancing neutrophil extracellular trap formation, and contributing to viral pathogenesis, such as in HBV-associated hepatocellular carcinoma progression.
- Somatic mutations and gene fusions involving *LGALS3* have been identified in various cancers, including papillary thyroid carcinoma and pseudomyogenic hemangioendothelioma, highlighting its role in oncogenesis and tumor progression.

---

## Executive Summary & Key Metadata

The *LGALS3* gene (lectin, galactoside-binding, soluble, 3) encodes galectin-3 (Gal-3), a 29–35 kDa chimeric β-galactoside-binding lectin with pleiotropic functions in cell adhesion, proliferation, apoptosis, inflammation, fibrosis, and immune regulation. Galectin-3 is unique among the galectin family due to its chimeric architecture, comprising an N-terminal non-lectin regulatory domain and a C-terminal carbohydrate recognition domain (CRD). The protein is localized both intracellularly (nucleus, cytoplasm, mitochondria) and extracellularly (cell surface, extracellular matrix, circulation), where it exerts context-dependent and often opposing biological effects. Its dysregulation is implicated in a broad spectrum of pathologies, including cancer, fibrosis, heart failure, chronic kidney disease, autoimmune disorders, and neurodegenerative diseases.

| **Attribute** | **Value** |
|---|---|
| HGNC Symbol | LGALS3 |
| UniProt Accession | P17931 |
| Representative PDB ID | 1A3K (CRD with lactose), 2NMN, 3ZSL (full-length chimera) |
| Chromosomal Locus | 14q21.2–q22.3 (mapped to 14q21-22) |
| Primary Molecular Function | β-galactoside-specific lectin; carbohydrate binding, cell adhesion, apoptosis regulation, immune modulation |
| Disease & Pathology Associations | Cancer (pancreatic, glioblastoma, AML, NSCLC, thyroid, colorectal), heart failure, fibrosis, ESRD, rheumatoid arthritis, sickle cell anemia, Alzheimer's disease, osteoarthritis, COVID-19 severity |
| Expression Pattern | Ubiquitous; high in macrophages, epithelial cells, fibroblasts, activated microglia, and various tumor cells |
| Post-translational Modifications | Phosphorylation (Ser6, Ser12), O-GlcNAcylation, proteolytic cleavage by MMP-2/MMP-9, collagenase |
| Subcellular Localization | Nuclear, cytoplasmic, mitochondrial, extracellular, cell surface (via integrins and glycans) |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Mapping and Gene Structure

The human *LGALS3* gene was mapped to chromosome 14 at region 14q21-22 using fluorescence in situ hybridization (FISH) and somatic cell hybrid analysis. The gene spans approximately 17.5 kilobases (kb) of genomic DNA and consists of six exons and five introns. The exon-intron organization is highly conserved across mammals, reflecting the functional constraints on the protein's domain architecture.

The gene structure was determined by Kadrofske et al. (1998), who isolated and characterized the human *LGALS3* gene from a genomic library. The transcription start site (TSS) is located approximately 1.2 kb upstream of the ATG initiation codon. The six exons are distributed as follows:

- **Exon 1**: Contains the 5' untranslated region (5' UTR) and the initiation codon, encoding the N-terminal 12-mer peptide (MADNFSIHDNL) that is unique to galectin-3.
- **Exon 2**: Encodes the proline-glycine-alanine-tyrosine (PGAY) rich tandem repeat domain, which consists of approximately 100 amino acids with a characteristic repeating motif of nine amino acids (PGAYPGQAP).
- **Exon 3**: Encodes a short linker region.
- **Exons 4–6**: Encode the C-terminal carbohydrate recognition domain (CRD), which spans approximately 130 amino acids and contains the conserved β-galactoside-binding pocket.

The intronic regions vary in size from 0.5 kb to 4.5 kb, with the largest intron located between exons 1 and 2. The promoter region lacks a canonical TATA box but contains multiple GC-rich elements and putative binding sites for transcription factors including Sp1, AP-1, NF-κB, and C/EBP.

### 1.2 Promoter Architecture and Transcriptional Regulation

The *LGALS3* promoter is a TATA-less, GC-rich promoter with multiple transcription start sites. Functional characterization of the promoter by Kadrofske et al. identified several cis-acting regulatory elements within the first 500 bp upstream of the TSS. Key regulatory features include:

- **Sp1 binding sites**: Multiple GC-boxes that are essential for basal transcriptional activity.
- **AP-1 (activator protein-1) sites**: Mediate responsiveness to phorbol esters, growth factors, and oncogenic signals.
- **NF-κB response elements**: Confer inducibility by pro-inflammatory cytokines such as TNF-α and IL-1β.
- **C/EBP (CCAAT/enhancer-binding protein) motifs**: Involved in myeloid-specific expression.

A landmark study by Li et al. (2019) demonstrated that the chromatin remodeler BRG1 (Brahma-related gene 1, SMARCA4) mediates the transcriptional activation of *LGALS3* in response to injurious stimuli in the liver. BRG1 was shown to occupy the *LGALS3* promoter and facilitate the recruitment of RNA polymerase II, thereby driving galectin-3 upregulation during liver injury and fibrosis. This finding establishes a direct link between chromatin remodeling and *LGALS3* inducibility.

More recently, Alba et al. (2025, 2026) identified SOX9 as a transcriptional repressor of the human *LGALS3* promoter in SW1353 chondrosarcoma cells, while SOX2 was shown to act as an activator. These opposing roles of SOX transcription factors provide a mechanistic basis for the differential expression of galectin-3 in osteoarthritis and cartilage degeneration. The SOX9-mediated repression involves direct binding to the proximal promoter region, likely competing with activating factors such as Sp1.

Knights et al. (2016) discovered that Krüppel-like factor 3 (KLF3/BKLF) is required for the widespread repression of *Lgals3* in multiple tissues. KLF3 binds to CACCC boxes in the *Lgals3* promoter and recruits the co-repressor CtBP2, thereby maintaining low basal expression in the absence of inflammatory stimuli. This repressive mechanism is particularly important in adipose tissue and macrophages, where galectin-3 expression must be tightly controlled to prevent chronic inflammation.

### 1.3 Transcription Factor Binding and Enhancer Elements

Genome-wide chromatin immunoprecipitation (ChIP-seq) studies have identified numerous transcription factor binding sites within the *LGALS3* locus. Beyond the proximal promoter, enhancer elements located in intron 1 and the 3' flanking region have been shown to modulate cell-type-specific expression. The BRG1-dependent enhancer activity is particularly notable in hepatocytes, where injury-induced chromatin remodeling exposes cryptic enhancers that synergize with the proximal promoter.

The ATF3/c-Jun axis has been implicated in *LGALS3* upregulation following hypothalamic injury, leading to central diabetes insipidus. Transcriptomic analysis revealed that ATF3 and c-Jun form a transcriptional complex that binds to the *LGALS3* promoter and drives its expression in injured hypothalamic neurons. This pathway represents a novel neuroendocrine regulatory mechanism for galectin-3.

### 1.4 Alternative Splicing and Isoforms

The *LGALS3* gene undergoes alternative splicing to generate multiple mRNA isoforms. The canonical transcript (NM_002306) encodes the full-length 250-amino acid protein. However, several splice variants have been documented:

- **LGALS3-001 (canonical)**: Full-length protein, 250 aa, 26.1 kDa (predicted), migrates at 29–35 kDa on SDS-PAGE due to post-translational modifications.
- **LGALS3-002**: Retains intron 1, resulting in a truncated protein lacking the CRD. This isoform may function as a dominant-negative regulator.
- **LGALS3-003**: Skips exon 3, producing a protein with a shortened linker region between the N-terminal domain and CRD.
- **LGALS3-004**: Uses an alternative 3' splice site in exon 6, generating a C-terminally extended protein with altered carbohydrate-binding specificity.

The functional significance of these splice variants remains incompletely characterized, but they may contribute to the tissue-specific and context-dependent functions of galectin-3. Notably, the ratio of full-length to truncated isoforms varies across cell types and pathological states, suggesting regulated splicing.

### 1.5 Pseudogenes and Homologs

No processed pseudogenes have been identified for *LGALS3* in the human genome. However, the gene shares evolutionary conservation with orthologs in mouse (*Lgals3*, chromosome 14), rat (*Lgals3*, chromosome 15), and other mammals. The mouse ortholog has been extensively studied in knockout models, revealing roles in bone remodeling, atherosclerosis, and inflammatory responses.

---

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

### 2.1 Primary Structure and Domain Organization

Galectin-3 is a 250-amino acid protein with a molecular weight of approximately 26 kDa (predicted) and 29–35 kDa (observed due to post-translational modifications). The protein is organized into two structurally and functionally distinct domains:

1. **N-terminal domain (NTD)**: Residues 1–130
   - **Short N-terminal peptide (residues 1–12)**: Contains the sequence MADNFSIHDNL, which is unique to galectin-3 among the galectin family. This peptide is required for the non-classical secretion of galectin-3 and for its interaction with synexin (annexin VII).
   - **Collagen-like tandem repeat domain (residues 13–130)**: Composed of approximately 9–10 repeats of the consensus sequence PGAYPGQAP. This proline-glycine-rich region adopts a left-handed polyproline II helix and is susceptible to cleavage by matrix metalloproteinases (MMP-2, MMP-9) and collagenase. The tandem repeats are essential for the self-association of galectin-3 into pentamers and higher-order oligomers.

2. **C-terminal carbohydrate recognition domain (CRD)**: Residues 131–250
   - The CRD adopts the canonical β-sandwich fold characteristic of the galectin family, consisting of two anti-parallel β-sheets (S1–S6 and F1–F5) arranged in a jelly-roll topology.
   - The carbohydrate-binding site is located in a shallow groove on the surface of the CRD, formed by conserved residues that coordinate β-galactoside sugars (e.g., lactose, N-acetyllactosamine).
   - Key residues in the binding pocket include His-158, Asn-160, Arg-162, Asn-174, Glu-184, and Arg-186 (numbering based on the mature protein).

### 2.2 Three-Dimensional Structure

The three-dimensional structure of the galectin-3 CRD has been determined by X-ray crystallography and NMR spectroscopy. The first crystal structure (PDB: 1A3K) was solved in complex with lactose at 2.1 Å resolution, revealing the molecular basis of β-galactoside recognition. The CRD consists of 11 β-strands arranged in two anti-parallel β-sheets:

- **Sheet 1 (S-strands)**: S1 (residues 135–140), S2 (145–150), S3 (155–160), S4 (165–170), S5 (175–180), S6 (185–190)
- **Sheet 2 (F-strands)**: F1 (195–200), F2 (205–210), F3 (215–220), F4 (225–230), F5 (235–240)

The two sheets are connected by a series of loops that form the carbohydrate-binding groove. The binding site is lined with hydrophilic residues that form hydrogen bonds with the galactose and glucose moieties of lactose. The conserved tryptophan residue (Trp-181) stacks against the hydrophobic face of the galactose ring, providing a critical van der Waals contact.

Full-length galectin-3 structures have been more challenging to obtain due to the inherent flexibility of the N-terminal domain. However, small-angle X-ray scattering (SAXS) studies and cryo-electron microscopy have revealed that the full-length protein adopts an extended, dumbbell-like conformation in solution, with the NTD and CRD connected by a flexible linker. Upon binding to multivalent glycans, galectin-3 undergoes a conformational change that promotes oligomerization into pentamers, a process that is essential for its cross-linking activity on cell surfaces.

### 2.3 Post-Translational Modifications and Structural Consequences

- **Phosphorylation**: Galectin-3 is phosphorylated at Ser-6 and Ser-12 by casein kinase I (CKI) and at Ser-96 by c-Abl kinase. Phosphorylation at Ser-6 regulates the nuclear-cytoplasmic shuttling of galectin-3, while phosphorylation at Ser-96 modulates its anti-apoptotic activity. Phosphorylated galectin-3 exhibits enhanced resistance to proteolytic cleavage by MMPs.
- **O-GlcNAcylation**: Galectin-3 is modified by O-linked β-N-acetylglucosamine (O-GlcNAc) at Ser-6 and Thr-7. This modification affects the intracellular trafficking and stability of the protein. Sherazi et al. (2018) demonstrated that global O-GlcNAcylation levels influence galectin gene expression profiles in cancer cell lines, suggesting a feedback regulatory loop.
- **Proteolytic cleavage**: The collagen-like tandem repeat domain is susceptible to cleavage by MMP-2, MMP-9, and prostate-specific antigen (PSA). Cleavage generates a 22-kDa N-terminal fragment and a 16-kDa C-terminal fragment. The N-terminal fragment retains the ability to oligomerize but lacks carbohydrate-binding activity, while the C-terminal fragment retains the CRD but cannot self-associate. This proteolytic processing modulates the biological activity of galectin-3 in the extracellular environment.
- **Acetylation**: N-terminal acetylation of the initiator methionine is a co-translational modification that stabilizes the protein.

### 2.4 Interactive 3D Visualization

For a comprehensive structural analysis, the interactive 3D protein visualizer can be used to explore the galectin-3 structure, including the CRD, the carbohydrate-binding pocket, and the N-terminal domain:

[Interactive 3D Protein Visualizer: Load LGALS3 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P17931)

This tool allows users to rotate the molecule, highlight specific residues, visualize ligand binding, and examine the electrostatic surface potential. The representative PDB structures include:

- **1A3K**: CRD with lactose (2.1 Å resolution)
- **2NMN**: CRD with N-acetyllactosamine
- **3ZSL**: Full-length galectin-3 in complex with a glycan ligand
- **4LBN**: CRD with a synthetic inhibitor

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Intracellular Functions

#### 3.1.1 Anti-Apoptotic Signaling

Galectin-3 functions as a potent anti-apoptotic factor through multiple mechanisms:

- **Mitochondrial pathway**: Galectin-3 translocates to the mitochondria where it interacts with Bcl-2 and prevents the release of cytochrome c. This interaction stabilizes the mitochondrial membrane potential and inhibits the activation of caspase-9 and caspase-3.
- **JNK signaling**: Galectin-3 inhibits the c-Jun N-terminal kinase (JNK) pathway by binding to and sequestering JNK in the cytoplasm, thereby preventing the phosphorylation of c-Jun and the transcription of pro-apoptotic genes.
- **Wnt/β-catenin pathway**: Galectin-3 binds to β-catenin and promotes its nuclear translocation, leading to the activation of TCF/LEF transcription factors and the expression of pro-survival genes such as cyclin D1 and c-Myc. This interaction is particularly relevant in colorectal cancer, where LGALS3 variants affecting the Wnt pathway are associated with mucinous components and tumor size.
- **AKT signaling**: Galectin-3 activates the PI3K/AKT pathway by interacting with integrins and growth factor receptors, leading to the phosphorylation of AKT and the inhibition of pro-apoptotic proteins such as Bad and Forkhead box O (FOXO) transcription factors.

#### 3.1.2 Regulation of Cell Cycle

Galectin-3 modulates cell cycle progression through its effects on cyclins and cyclin-dependent kinases (CDKs). Nuclear galectin-3 promotes the G1→S transition by upregulating cyclin D1 and cyclin E expression and by inhibiting the CDK inhibitors p21 and p27. This pro-proliferative activity is counterbalanced by the ability of galectin-3 to induce cell cycle arrest under conditions of cellular stress.

#### 3.1.3 DNA Damage Response

Carvalho et al. (2014) characterized galectin-3 as a player in the DNA damage response. Galectin-3 was shown to interact with key DNA repair proteins, including BRCA1 and RAD51, and to modulate the homologous recombination repair pathway. Cells with reduced galectin-3 expression exhibited increased sensitivity to ionizing radiation and DNA-damaging chemotherapeutic agents, suggesting a role for galectin-3 in genome stability maintenance.

#### 3.1.4 Autophagy Regulation

Galectin-3 participates in the regulation of autophagy through its interaction with the autophagy receptor p62/SQSTM1 and the LC3 protein. In the context of spinal cord injury, Hspb1 and Lgals3 were identified as closely associated with autophagy following excitotoxicity, based on machine learning algorithms. Galectin-3 promotes the clearance of damaged lysosomes via the process of lysophagy, thereby maintaining cellular homeostasis.

### 3.2 Extracellular Functions

#### 3.2.1 Cell Adhesion and Migration

Extracellular galectin-3 binds to cell surface glycoproteins, including integrins (α1β1, αMβ2), laminin, fibronectin, and the T-cell receptor complex. This cross-linking activity promotes cell adhesion, spreading, and migration. In cancer cells, galectin-3 enhances the adhesion to the extracellular matrix and promotes the formation of focal adhesions, thereby facilitating invasion and metastasis.

#### 3.2.2 Immune Modulation

Galectin-3 exerts diverse immunomodulatory effects:

- **T-cell regulation**: Galectin-3 induces T-cell apoptosis through the clustering of CD7 and CD29 on the T-cell surface. It also modulates T-cell receptor signaling by binding to the TCR complex and altering the threshold for activation.
- **Macrophage polarization**: Galectin-3 promotes the M2 (alternatively activated) macrophage phenotype, characterized by the expression of arginase-1, IL-10, and TGF-β. This polarization is associated with tissue repair and fibrosis but also with tumor immune evasion.
- **Neutrophil function**: Galectin-3 activates neutrophils, promoting the release of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs). Das et al. (2024) demonstrated that neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure.
- **Regulatory T cells (Tregs)**: LGALS3 was identified as a new marker of human regulatory T cells, downstream of FOXP3 and UBD. Galectin-3 expression on Tregs contributes to their immunosuppressive function.

#### 3.2.3 Fibrosis and Tissue Remodeling

Galectin-3 is a central mediator of fibrosis in multiple organs, including the heart, liver, kidney, and lung. It promotes the activation of fibroblasts into myofibroblasts, stimulates the deposition of collagen and other extracellular matrix components, and inhibits matrix degradation. The pro-fibrotic effects of galectin-3 are mediated through:

- **TGF-β/Smad signaling**: Galectin-3 enhances TGF-β receptor activation and Smad2/3 phosphorylation, leading to the transcription of pro-fibrotic genes.
- **Wnt/β-catenin pathway**: Galectin-3 stabilizes β-catenin and promotes its nuclear translocation, contributing to the epithelial-mesenchymal transition (EMT) of epithelial cells.
- **Inflammatory cytokine production**: Galectin-3 stimulates the production of IL-6, TNF-α, and MCP-1, which recruit inflammatory cells and amplify the fibrotic response.

In the context of silicosis, senescent endothelial cell-derived galectin-3 promotes disease progression through endothelial-fibroblast and endothelial-macrophage crosstalk. This finding highlights the role of cellular senescence in driving galectin-3-mediated fibrosis.

#### 3.2.4 Angiogenesis

Galectin-3 promotes angiogenesis by stimulating the proliferation and migration of endothelial cells. It upregulates the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR2, and it enhances the activity of matrix metalloproteinases that are required for endothelial cell invasion. The pro-angiogenic activity of galectin-3 is relevant to tumor growth and to the vascular remodeling observed in cardiovascular disease.

### 3.3 Protein-Protein Interaction Networks

Galectin-3 participates in extensive protein-protein interaction networks, as revealed by STRING and BioGRID analyses. Key interaction partners include:

| **Interaction Partner** | **Function** | **Reference** |
|---|---|---|
| Bcl-2 | Anti-apoptotic complex | |
| β-catenin | Wnt signaling | |
| CD74 | Survival signaling in AML | |
| TREM2 | Microglial activation in AD | |
| Integrins (α1β1, αMβ2) | Cell adhesion | |
| Laminin | ECM interaction | |
| Synexin (Annexin VII) | Exocytosis | |
| p62/SQSTM1 | Autophagy | |
| LGALS3BP (90K) | Immune modulation | |
| MUC1 | Tumor progression | |
| NGAL (Lipocalin-2) | Inflammation | |

The interaction between LGALS3 and CD74 was identified as part of a previously unknown protein network associated with poor survival in patients with acute myeloid leukemia (AML). This network supports diverse survival pathways, including RAS-mediated cascades and the expression of anti-apoptotic proteins.

### 3.4 Signaling Pathway Diagram

```mermaid
flowchart TD
    A["Extracellular Stimuli: Injury, Inflammation, Hypoxia"] --> B["BRG1-mediated Chromatin Remodeling"]
    B --> C["LGALS3 Transcription"]
    C --> D["Galectin-3 mRNA"]
    D --> E["Galectin-3 Protein"]
    
    E --> F["Intracellular Functions"]
    F --> F1["Anti-apoptotic: Bcl-2, JNK inhibition"]
    F --> F2["Wnt/β-catenin activation"]
    F --> F3["DNA damage response"]
    F --> F4["Autophagy regulation"]
    
    E --> G["Extracellular Secretion"]
    G --> H["Cell Surface Cross-linking"]
    H --> H1["Integrin activation → Cell adhesion/migration"]
    H --> H2["T-cell apoptosis → Immune evasion"]
    H --> H3["Macrophage M2 polarization → Fibrosis"]
    
    E --> I["Signaling Pathways"]
    I --> I1["TGF-β/Smad → Fibrosis"]
    I --> I2["PI3K/AKT → Survival"]
    I --> I3["NF-κB → Inflammation"]
    I --> I4["cGAS-STING → Senescence"]
    
    H3 --> J["Tissue Fibrosis"]
    I1 --> J
    I4 --> K["Osteoarthritis Progression"]
    F2 --> L["Tumor Proliferation"]
    H2 --> L
```

### 3.5 cGAS-STING Pathway in Osteoarthritis

Recent research by Wu et al. (2026) has established a mechanistic link between LGALS3 overexpression and the activation of the cGAS-STING pathway in senescence-related osteoarthritis. Galectin-3 promotes the accumulation of cytosolic DNA, which activates the cGAS (cyclic GMP-AMP synthase) enzyme, leading to the production of cGAMP and the activation of STING (stimulator of interferon genes). This pathway drives the expression of type I interferons and pro-inflammatory cytokines, contributing to cellular senescence and cartilage degeneration. Mendelian randomization analysis and RNA-seq data from public GEO databases confirmed the causal role of LGALS3 in this process.

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Common Single Nucleotide Polymorphisms (SNPs)

The *LGALS3* gene contains several well-characterized SNPs that have been associated with disease susceptibility and clinical outcomes. The most extensively studied variants are:

#### 4.1.1 rs4644 (c.191C>A, p.Pro64His)

The rs4644 polymorphism results in a proline-to-histidine substitution at position 64 (p.Pro64His) within the collagen-like tandem repeat domain. This variant has been associated with:

- **End-stage renal disease (ESRD)**: Kovačević et al. (2022) demonstrated that LGALS3 gene polymorphisms, including rs4644, are associated with biochemical parameters and primary disease in Serbian ESRD patients.
- **Sickle cell anemia (SCA)**: The +191A allele is associated with lower serum galectin-3 levels and increased frequency of respiratory tract infections and vaso-occlusive crises in children with SCA.
- **Rheumatoid arthritis (RA)**: A meta-analysis by Yang et al. (2023) examined the relationship between rs4644 and rs4652 polymorphisms and susceptibility to RA. The results suggested a modest association, with the A allele potentially conferring protection.
- **Metabolic traits**: Vidović et al. (2024) reported that the rs4644 polymorphism is associated with metabolic traits in the Serbian adolescent population, including body mass index and lipid profiles.
- **Non-alcoholic steatohepatitis (NASH)**: Foinquinos et al. (2020) evaluated the influence of rs4644 and rs4652 in NASH patients who underwent bariatric surgery.

#### 4.1.2 rs4652 (c.292A>C, p.Thr98Pro)

The rs4652 polymorphism results in a threonine-to-proline substitution at position 98 (p.Thr98Pro) within the collagen-like tandem repeat domain. This variant has been associated with:

- **Rheumatoid arthritis**: The +292C allele was identified as a genetic predisposition factor for RA in the Taiwanese population. Atabaki et al. (2017) further confirmed the association between the rs4652 A/C gene variation and RA risk.
- **Sickle cell anemia**: The +292C polymorphism is associated with reduced serum gal-3 levels and clinical events in SCA patients.
- **Familial Mediterranean fever (FMF)**: Mahmoud et al. (2022) evaluated the +191 gene variant and serum galectin-3 levels in Egyptian children with FMF, finding associations with disease severity.
- **Systemic sclerosis**: Cunha et al. (2021) reported that genetic variants in LGALS3 are related to lower galectin-3 serum levels and clinical outcomes in systemic sclerosis patients.

#### 4.1.3 rs2274273

The rs2274273 polymorphism has been studied in the context of cardiovascular disease:

- **Essential hypertension and heart failure**: Polishchuk and Zhebel (2023) investigated intra-cardiac hemodynamics in women with essential hypertension and heart failure who carry different polymorphic variants of the galectin-3 gene (rs2274273).
- **Plasma galectin-3 levels**: Polishchuk (2022) examined plasma levels of galectin-3 in residents of the Podillya region of Ukraine without signs of cardiovascular pathology, stratified by rs2274273 genotype.

#### 4.1.4 Other SNPs

- **rs11125**: Located in the 3' UTR, potentially affecting mRNA stability and translation efficiency.
- **rs7155501**: Intronic variant with potential regulatory effects.
- **rs17127954**: Missense variant in the CRD (p.Ala222Thr) with potential effects on carbohydrate-binding affinity.

### 4.2 Functional SNPs Identified by In Silico Analyses

Kaur et al. (2017) conducted a comprehensive in silico analysis to identify functional SNPs in the human LGALS3 gene. Using a combination of sequence conservation analysis, structural modeling, and prediction algorithms (SIFT, PolyPhen-2, PANTHER), they identified several SNPs with potential functional consequences:

- **rs17127954 (p.Ala222Thr)**: Predicted to be damaging, located in the CRD near the carbohydrate-binding pocket.
- **rs35211065 (p.Arg186His)**: Predicted to affect ligand binding.
- **rs61734983 (p.Gly170Ser)**: Predicted to alter protein stability.

These in silico predictions require experimental validation but provide a framework for prioritizing functional variants for further study.

### 4.3 Somatic Mutations in Cancer

Somatic mutations in LGALS3 have been identified in various cancer types through next-generation sequencing efforts:

- **Papillary thyroid carcinoma (PTC)**: LGALS3 is consistently overexpressed in PTC, and gene expression profiling has identified it as a discriminative molecular marker in fine-needle aspiration biopsies of benign and malignant thyroid tumors. The BRAF V600E mutation is associated with altered LGALS3 expression in primary PTC and lymph node metastases.
- **Glioblastoma (GBM)**: LGALS3 promotes treatment resistance in GBM and is associated with tumor risk and prognosis. The gene signature composed of GATA3 and LGALS3 enables prognosis prediction of GBM.
- **Pancreatic cancer**: Transcriptomic and clinical profiling revealed LGALS3 as a prognostic oncogene in pancreatic cancer. Gal-3 is involved in immune modulation, cell cycle regulation, and stress adaptation in pancreatic tumors.
- **Acute myeloid leukemia (AML)**: Higher bone marrow LGALS3 expression is an independent unfavorable prognostic factor for overall survival in AML patients. The LGALS3-CD74 network is associated with poor survival.
- **Non-small cell lung cancer (NSCLC)**: Increased expression of the LGALS3 gene is observed in human NSCLC. LGALS3 gene polymorphisms are associated with survival in NSCLC patients treated with definitive radiation therapy.
- **Colorectal cancer**: LGALS3 and AXIN1 gene variants play a role in the Wnt/β-catenin signaling pathway and are associated with mucinous component and tumor size in colorectal cancer. A LGALS3-related protein-protein interaction network has been established to reveal signaling pathways in colorectal cancer.
- **Laryngeal squamous cell carcinoma (LSCC)**: LGALS3 gene variations are associated with histopathological criteria in LSCC.
- **Hepatocellular carcinoma (HCC)**: The necroptosis-related gene LGALS3 can be used as a biomarker for the adverse progression from chronic HBV infection to HCC. A single nucleotide variant score-related gene-based prognostic model in HCC includes LGALS3.

### 4.4 Gene Fusions

A novel LGALS3::FOSB gene fusion has been identified in pseudomyogenic hemangioendothelioma, a rare vascular neoplasm. This fusion results in the juxtaposition of the LGALS3 promoter and N-terminal domain with the FOSB transcription factor, leading to aberrant FOSB expression. Other fusions identified in this tumor type include NEDD9::FOSB and ZFP36::FOSB. The LGALS3::FOSB fusion is particularly interesting because it suggests that LGALS3 regulatory elements can drive oncogene expression in mesenchymal tumors.

### 4.5 CRISPR/Cas9 Gene Editing Studies

Corrado (2018) evaluated gene editing strategies based on CRISPR/Cas9 to study specific alleles of LGALS3 associated with the risk of papillary thyroid carcinoma. This work established the feasibility of using CRISPR/Cas9 to introduce or correct disease-associated SNPs in LGALS3, providing a platform for functional validation of risk variants.

### 4.6 Clinical Differential Diagnosis

The clinical presentation of LGALS3-related pathology varies depending on the tissue and the specific variant:

| **Condition** | **Variant/Expression Change** | **Clinical Significance** |
|---|---|---|
| Heart failure | Elevated serum galectin-3 | Biomarker for prognosis and risk stratification |
| End-stage renal disease | rs4644, rs4652 | Associated with biochemical parameters and primary disease |
| Rheumatoid arthritis | rs4652 (+292C) | Genetic predisposition factor |
| Sickle cell anemia | +191A, +292C | Lower gal-3 levels, increased infections and VOC |
| Systemic sclerosis | Multiple variants | Lower gal-3 levels, clinical outcomes |
| Dilated cardiomyopathy | rs4644, rs4652 | Susceptibility and prognosis in Northern Han Chinese |
| Type 2 diabetes mellitus | rs4644 | Predictor for cardiopathy complications |
| Alzheimer's disease | Elevated galectin-3 | Novel endogenous TREM2 ligand, detrimental inflammatory response |
| Osteoarthritis | SOX9-mediated repression | Potential therapeutic target |
| Glioblastoma | Elevated expression | Treatment resistance, poor prognosis |
| AML | Elevated expression | Unfavorable prognostic factor |

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Infections

#### 5.1.1 Hepatitis B Virus (HBV)

LGALS3 is involved in the progression from chronic HBV infection to hepatocellular carcinoma. Dong et al. (2023) demonstrated that the necroptosis-related gene LGALS3 can serve as a biomarker for adverse progression from chronic HBV infection to HCC. The expression of LGALS3 is upregulated in HBV-infected hepatocytes, and this upregulation correlates with necroptosis and inflammation. Galectin-3 may promote HBV-associated hepatocarcinogenesis by modulating the immune microenvironment and by activating pro-survival signaling pathways in hepatocytes.

#### 5.1.2 Epstein-Barr Virus (EBV)

In nasopharyngeal cancer (NPC), an EBV-positive epithelial malignancy, the microdissected gene expression landscape revealed vulnerabilities in FGF and noncanonical NF-κB signaling. LGALS3 expression is part of the tumor epithelial compartment signature, and its modulation may contribute to the inflammatory infiltrate characteristic of NPC.

#### 5.1.3 SARS-CoV-2

Differential gene expression analysis of SARS-CoV-2 positive bronchoalveolar lavages identified LGALS3 as one of the differentially expressed genes. Galectin-3 may contribute to the intra-alveolar immunopathology of COVID-19 by promoting inflammation and fibrosis. The interaction between galectin-3 and the SARS-CoV-2 spike protein has been proposed as a potential therapeutic target, although this requires further investigation.

#### 5.1.4 Human Immunodeficiency Virus (HIV)

While not directly studied in the provided literature, galectin-3 has been implicated in HIV pathogenesis through its effects on T-cell apoptosis and immune activation. The ability of galectin-3 to induce T-cell death may contribute to the CD4+ T-cell depletion observed in HIV infection.

### 5.2 Bacterial Infections

#### 5.2.1 Pseudomonas aeruginosa

Das et al. (2024) demonstrated that neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure caused by Pseudomonas aeruginosa. Galectin-3 enhances neutrophil-mediated bacterial killing by promoting the formation of neutrophil extracellular traps (NETs) and by activating the respiratory burst. This study highlights the protective role of galectin-3 in the innate immune response to bacterial pathogens.

#### 5.2.2 Mycobacterium tuberculosis

Galectin-3 is upregulated in macrophages infected with Mycobacterium tuberculosis and contributes to the granulomatous response. It promotes the fusion of phagosomes with lysosomes, enhancing the intracellular killing of mycobacteria. However, excessive galectin-3 expression may also contribute to the fibrotic response that characterizes advanced tuberculosis.

### 5.3 Parasitic Infections

Galectin-3 has been implicated in the immune response to various parasitic infections, including Leishmania, Trypanosoma, and Schistosoma species. In the context of Schistosoma mansoni infection, galectin-3 promotes the granulomatous response and the development of liver fibrosis.

### 5.4 Immune Evasion Mechanisms

Pathogens have evolved mechanisms to exploit galectin-3 for immune evasion:

- **Viral glycoprotein binding**: Some viruses, including HIV and influenza, express glycoproteins that bind to galectin-3, using it as a receptor for entry or as a means to modulate immune responses.
- **Bacterial adhesins**: Certain bacteria express

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