Galectin 3 (Gal-3) is a \(\beta\)-galactoside-binding lectin found ubiquitously throughout the human body. This protein binds to specific sugar structures, or glycans, on cell surfaces and in the surrounding matrix. Gal-3 is present inside cells, on cell membranes, and secreted into the bloodstream, acting as a versatile messenger in healthy biological processes. While its presence is normal, elevated concentrations are strongly associated with chronic diseases, primarily by driving uncontrolled inflammation and tissue scarring.
The Identity and Normal Function of Galectin 3
Galectin 3 is categorized as a chimera-type galectin. Its structure includes a long, flexible N-terminal domain connected to a C-terminal carbohydrate recognition domain (CRD). The CRD is responsible for binding to \(\beta\)-galactosides, such as N-acetyllactosamine, which are common sugar components on cell surface proteins.
The N-terminal domain allows multiple Gal-3 molecules to link together, forming multimeric structures. This cross-linking capability enables Gal-3 to orchestrate communication signals between the cell and the extracellular matrix.
Gal-3 is highly expressed by immune cells like macrophages and monocytes, playing a role in immune surveillance. It helps regulate the movement and activation of these cells during acute inflammatory responses. Intracellularly, Gal-3 also has an anti-apoptotic function, promoting cell survival.
Driving Chronic Inflammation and Tissue Remodeling
The pathological significance of Gal-3 emerges when its expression is persistently high, shifting its function from healthy repair to chronic disease promotion. Following tissue injury, such as a heart attack or liver damage, macrophages and injured cells secrete large amounts of Gal-3 into the local environment. While this initial surge is part of the wound healing process, the sustained presence of elevated Gal-3 signals a state of unresolved, chronic inflammation.
Extracellular Gal-3 acts as a pro-fibrotic molecule by directly activating quiescent fibroblasts, the cells responsible for maintaining tissue structure. This activation causes fibroblasts to transform into highly secretory cells called myofibroblasts. Myofibroblasts then produce and deposit excessive amounts of extracellular matrix proteins, most notably collagen.
Unchecked collagen deposition leads to fibrosis, forming scar tissue that stiffens the organ and impairs function. In the heart, this causes adverse ventricular remodeling and reduced pumping efficiency, a defining feature of heart failure. For the liver, Gal-3 activates hepatic stellate cells into myofibroblasts, accelerating the progression toward cirrhosis. Similarly, in the kidneys, elevated Gal-3 drives a profibrotic axis correlating directly with interstitial scarring and the progression of chronic kidney disease.
Galectin 3 as a Biomarker for Disease Risk
The consistent link between elevated circulating Gal-3 and fibrosis has established its value as a prognostic biomarker. Gal-3 concentration is typically measured in a blood sample using a standardized enzyme-linked immunosorbent assay (ELISA). A prognostic biomarker provides information about the likely future course of a disease and the risk of adverse events.
Its most established clinical application is in cardiovascular disease, where it is used to assess risk in patients with chronic heart failure (HF). Unlike natriuretic peptides, which primarily reflect acute hemodynamic stress and fluid overload, Gal-3 reflects the irreversible, chronic process of myocardial fibrosis. A plasma concentration exceeding the established cutoff of 17.8 ng/mL is associated with a significantly increased risk of hospitalization for heart failure and all-cause mortality.
Monitoring changes in Gal-3 levels over time provides predictive insight into disease trajectory. A sustained increase of 15% or more is an independent predictor of worsening outcomes. Beyond the heart, elevated Gal-3 is also used to assess the severity and progression of fibrosis in other organs. High levels correlate with reduced glomerular filtration rate in chronic kidney disease and indicate liver fibrosis progression in conditions like non-alcoholic steatohepatitis.
Therapeutic Strategies for Galectin 3 Inhibition
Gal-3’s role in driving tissue fibrosis has made it an attractive therapeutic target. The rationale for inhibition is to block the protein’s ability to bind to its sugar ligands, preventing the activation of fibroblasts and subsequent scarring. By interrupting this pro-fibrotic signaling pathway, researchers hope to halt or reverse organ damage.
Current research focuses on developing specific molecules that bind to Gal-3’s carbohydrate recognition domain. One class being investigated are small-molecule inhibitors, such as TD139 (GB0139). This compound was developed as an inhaled treatment and has progressed through clinical trials, primarily for idiopathic pulmonary fibrosis.
Another approach involves Modified Citrus Pectin (MCP), a natural product derived from citrus fruits. MCP contains galactose-rich fragments that bind to Gal-3, acting as a functional inhibitor. While preclinical studies show promise, clinical trials involving MCP have yielded mixed results regarding its effectiveness. Most therapeutic agents remain in the experimental or early clinical investigation phase, necessitating further research.