Galectins and Liver Diseases

1. Introduction

The discovery of galectin dates back to 1975, when Teichberg et al. discovered a low-molecular-weight (14–16 kDa) erythrocyte aggregate that could be inhibited by β-galactoside in various animal tissues, including those of electric eels. To the best of our knowledge, this is the first report on galactoside-binding lectins (galectins) [1]. Lectins are defined as “glycan-binding proteins that are neither enzymes nor antibodies” and are present in various tissues, where they play a key role in influencing cell fate [2]. Among endogenous soluble lectins, galectins are thought to interact extracellularly with cell-surface sugar chains, regulate signal transduction, and determine cell fate [3,4]. Galectins were originally identified in vertebrates; however, they are widely distributed in the animal kingdom, from sponges to mammals, with galectin-like domains also reported in viruses and plants [5].

Unlike many intracellular molecules and pathways that specialize in specific functions, galectins perform diverse immunological roles [6]. Many galectins can move between intracellular compartments (e.g., the nucleus, cytoplasm, and organelles) and are released into the extracellular environment [7]. Afterward, they acquire different roles in response to diverse microenvironmental stimuli, such as hypoxia, nutritional conditions, intra- and extracellular pH levels, cytokine environment, and inflammatory or immunosuppressive signals. Galectins have attracted increasing attention as diagnostic and therapeutic targets for diseases, such as fibrosis, cancer, and inflammatory conditions [8,9].

However, little is known about the involvement of galectins in liver disease. Here, we review the functions of various galectins and evaluate their roles in liver diseases.

2. Galectin Family

2.1. Structure of Galectins

Galectins are a family of soluble lectins that recognize glycans with β-galactosides. To date, 19 galectin subtypes have been identified [10]. These proteins contain one or two carbohydrate recognition domains (CRDs) per molecule and have similar amino acid sequences and structures [6,11,12,13]. However, each galectin exhibits different carbohydrate-binding specificities [14,15,16,17]. Galectins are classified into three subgroups, proto-, tandem-repeat, and chimeric, depending on the number and function of their CRDs (Figure 1a–c).

Prototypic galectins contain only one CRD and can dimerize via noncovalent binding (e.g., Gal-1, -2, -5, -7, -10, -11, -13, -14, -15). These galectins form homodimers, where two identical CRDs are held together by noncovalent electrostatic forces that are concentration-dependent and independent of ligand influence [18,19].

Tandem-repeat-type galectins have two distinct CRDs, each with different sugar-binding capacities, connected by 5–50 amino acids (Gal-4, -6, -8, -9, and -12) [18].

The only member of the chimeric galectins is Gal-3, which has a unique structure distinct from other galectin family members and can form pentamers [20,21,22,23]. High concentrations of Gal-3 monomers contributed to increased ligand-binding capacity and stability [12]. Chimeric galectins are characterized by a single C-terminal CRD and a large non-lectin N-terminal domain (approximately 120 amino acids) rich in proline, glycine, and tyrosine residues, which may contribute to Gal-3 oligomerization [18].

2.2. Functions of Galectin Structures

Galectins are an important family of β-galactoside-binding lectins that play a key role in regulating “cell-cell” and “cell-matrix” interactions [24,25,26]. Their interaction with specific ligands triggers diverse biological activities, depending on the cell type, tissue context, individual galectin expression levels, and receptors involved. Some galectin family members (e.g., Gal-1, -3, and-9) are widely expressed in various cells, including immune cells, endothelial cells, epithelial cells, and sensory neurons. For instance, Gal-7 is mainly localized in the skin; Gal-10 is strongly expressed in eosinophils and basophils; and Gal-12 is abundantly expressed in adipose tissue. Additionally, some galectins exhibit more restricted tissue localization, such as Gal-12 in adipose tissue [27]. Gal-1 and -3 are ubiquitously expressed, whereas Gal-4 is typically expressed in gastrointestinal epithelial cells. Notably, Gal-4 contains two CRDs with distinct binding specificities and functions that enable it crosslink molecules and regulate several biological processes [28]. Like many cytokines, galectins exhibit diverse actions that overlap with immunomodulatory activities. For cytokines, this diversity and overlap can be partly attributed to the fact that they share common signaling molecules. Regarding galectins, this diversity and redundancy may arise from their ability to bind ligands multivalently, as soluble galectins can cross-link ligands on the cell surface via at least three different (but not mutually exclusive) pathways [29]. Due to their diverse structures, galectins can bind to a wide range of ligands across multiple cellular pathways, including adhesion, aggregation, angiogenesis, apoptosis, autophagy, proliferation, and metastasis [30,31,32].

3. Functions of Galectins

3.1. Regulation of Immune Response

Galectins influence various immune cell processes via both intracellular and extracellular mechanisms [33]. They play significant roles in both innate and adaptive immune responses [34], regulating immune cell homeostasis during adaptive immune responses [35,36,37].

Galectins have diverse effects on the cells involved in innate immune responses [38,39]. Some key functions of galectins during the inflammatory response include influencing the ability of innate immune cells to respond to chemotactic gradients, migrate across the endothelium, synthesize and release pro- or anti-inflammatory cytokines, and recognize and eliminate pathogens and damaged cells [40].

Gal-1 induces the proliferation of activated T cells and B cells [41], macrophages [42], regulatory T cells (T-regs cells), and dendritic cells (DCs) [43]. Gal-1 also functions as a negative regulatory checkpoint for receptors involved in signal transduction [44,45,46]. Specifically, Gal-1 induces apoptosis of activated T cells by binding to the CD45 receptor [47]. Interestingly, activated T cells can produce Gal-1 through a MEK1/ERK and p38 MAP kinase signaling-dependent pathway, suggesting an autocrine suicide mechanism to terminate effector immune responses [48]. Furthermore, Gal-1 plays a role in moderating Th1- and Th17-mediated responses, directing the immune response toward a Th2-type profile [49,50].

Gal-3 helps regulate key biological processes, such as regeneration, cell migration, and immune responses [51,52]. It is localized on the cell surface, within the cytoplasm, and in the nucleus, and it can also be secreted into the extracellular space and systemic circulation [51,52].

Recent studies have demonstrated that Gal-3 plays an important role in modulating immune responses by suppressing T-cell activity [51,53,54,55,56]. Specifically, extracellular Gal-3 affects the formation of immune synapses, thereby attenuating T-cell activation. Moreover, intracellular Gal-3 interacts with various membrane lipids and proteins, affecting processes such as endocytosis and signaling via T cell receptors. [57,58].

Gal-9 acts as a selective chemoattractant for eosinophils and is highly expressed in various immune system tissues, including the bone marrow, spleen, thymus, and lymph nodes. Gal-9 released from activated T cells induces eosinophil chemotaxis, activation, oxidative activity, degranulation, and monocyte-derived DC maturation [44,59,60]. Gal-9 also promotes tissue inflammation by interacting with the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3) in macrophages [61]. Gal-9 also contributes to innate immunity by promoting DC maturation, as evidenced by the increased expression of Th1 cytokines and co-stimulatory molecules such as HLA-DR, CD83, CD80, CD54, and CD40 [62]. These mature DCs subsequently migrate to the lymph nodes, where they trigger T cell activation. Additionally, Gal-9 acts as a chemotactic agent for eosinophils, regulates signal-dependent chemotaxis of neutrophils, and enhances phagocytosis [63,64]. In monocytes, intracellular Gal-9 induces the transcription of pro-inflammatory cytokines such as IL-1α, IL-1β, and IFN-γ [65]. Conversely, Gal-9 promotes the proliferation of immunosuppressive macrophages [66,67].

3.2. Apoptosis

Apoptosis is a type of programmed cell death, which is characterized by morphological changes that occur in response to exogenous and endogenous stresses [68]. Apoptosis occurs during normal tissue development and morphogenesis [69]. Once apoptosis is initiated, the cell membrane remains stable, preventing the release of cytokines and other pro-inflammatory substances from the disrupted cells, thereby weakening inflammation and tissue damage [70].

In vivo studies have shown that extracellular Gal-1 binds to glycan molecules expressed on the surface of eosinophils, induces cell death via apoptosis, and inhibits cell migration [71]. Gal-1 also induces T cell apoptosis [72]. Gal-9, a tandem-repeat member of the galectin family, primarily functions as an anti-inflammatory lectin and promotes Th1 and Th17 cell apoptosis by interacting with Tim-3 [73]. Additionally, Gal-9 plays a role in the dysregulation of apoptotic mechanisms during oncogenesis and directly induces apoptosis in gastrointestinal cancer cells [9].

3.3. Angiogenesis

Galectins are multifaceted molecules that exhibit immunomodulatory and pro-angiogenic functions [74]. Gal-1 binds to VEGFR2 and neuropilin-1 in endothelial cells, promoting angiogenesis [75] and mimicking the effects of VEGF. The inhibition of Gal-1 binding to complex N-glycans attenuates both cancer-induced immunosuppression and angiogenesis. Furthermore, the early targeting of this lectin during tumor progression promotes vascular normalization, alleviating tumor hypoxia and increasing the influx of immune cells into the tumor microenvironment [76]. On the other hand, Gal-3 promotes angiogenesis by binding to integrins αvβ3 [77]. In addition, Gal-8 promotes angiogenesis through the cross-linking of activated leukocyte cell adhesion molecules and facilitates lymphangiogenesis by binding to podoplanin and integrins [78]. These interactions between galectins and glycans affect tumor angiogenesis by engaging different receptors and signaling pathways.

3.4. Fibrosis

Fibrosis represents the final common pathway in chronic tissue damage. Chronic inflammation, scar tissue formation, loss of tissue structure, and organ failure are hallmarks of the etiology of many human diseases and major causes of morbidity and mortality worldwide [79]. Fibroblasts and myofibroblasts are key cells involved in initiating and perpetuating organ scarring [80]. Gal-3 contributes to the initiation and amplification of acute inflammatory responses by mobilizing macrophages to the site of injury and perpetuating a chronic inflammatory state through pro-inflammatory pathways. This can lead to fibrosis due to unresolved inflammation and abnormal tissue repair. In an experimental model of liver fibrosis, a close spatial and temporal relationship was observed among Gal-3 expression, myofibroblast activation, and collagen deposition. Gal-3 can be considered an immediate early gene that is rapidly upregulated in response to tissue damage [81]. Gal-3 plays an important role in the pathological remodeling of the myocardium following cardiac injury, chronic stress, or inflammation, subsequently contributing to myocardial fibrosis, a hallmark of atrial fibrillation and heart failure [82,83,84,85,86].

4. Galectins and Medicine

4.1. Galectins as Disease Biomarkers

In 2014, the U.S. and FDA included Gal-3 on their list of validated cardiovascular biomarkers [85]. Elevated serum Gal-3 levels have been observed in almost all types of cardiovascular diseases, and their prognostic value for various clinical outcomes has been extensively studied [87,88,89]. A positive association between Gal-3 levels and the incidence of heart failure has been demonstrated [90,91]. Gal-3 serves as a valuable prognostic marker for both acute and chronic heart failure [92]. Higher Gal-3 levels indicate an increased risk of all-cause and cardiovascular mortality, as well as a higher risk of complications [93].

Gal-9 is expressed in various tumors, including those of the liver, small intestine, thymus, kidney, spleen, lung, heart, and skeletal muscle [94]. Gal-3 is expressed in the thyroid gland [95,96,97], stomach [98], colorectal tissue [99], and pancreatic cancers [100]. It is also a diagnostic and prognostic marker for breast cancer. Gal-3 expression is redistributed from the luminal epithelial cells in the more invasive ducts to the peripheral epithelial cells [97]. In melanoma, Gal-3 accumulates in the nuclei of melanocytes as the disease progresses [101]. Recently, Gal-4 was found to be involved in the peritoneal metastasis of malignant gastric cancer cells by interacting with several molecules, including c-MET and CD44, and influencing glycosylation [102,103,104].

Galectins have great potential as biomarkers. However, galectins are considered limited biomarkers due to large gaps in sensitivity and specificity between different subtypes, and their value is further limited by the lack of population data and variability in genetic and environmental factors [105].

4.2. Application as a Therapeutic Target

Galectins play important roles in tumor development, progression, and metastasis [106,107]. They are generally considered potential therapeutic targets, and many galectin inhibitors have been developed, some of which have been validated in clinical trials [108]. Endothelial cells are particularly appealing targets as they are directly accessible through the bloodstream, allowing circulating drugs to reach them easily [109]. Furthermore, targeting galectins in the vasculature may provide dual benefits by inhibiting tumor angiogenesis while simultaneously alleviating immunosuppression. This dual effect is supported by numerous studies showing that targeting galectins inhibits tumor progression by reducing tumor angiogenesis and stimulating anti-tumor immune responses [110,111,112,113].

Recently, therapies targeting immune checkpoints have gained momentum, unleashing anti-tumor immunity and providing significant clinical benefits to patients with various malignancies. Galectins are emerging as novel regulatory checkpoints that promote immune evasion by inducing T cell exhaustion, limiting T cell survival, promoting regulatory T cell proliferation, inactivating natural killer cells, and polarizing bone marrow cells toward immunosuppressive phenotypes. [13,114,115,116]

5. Expression Patterns and Roles of Galectins in the Liver

Gal-1, -3, and -9 are particularly well-reported galectins expressed in the liver. Gal-1 is widely expressed in the liver, especially in activated hepatic stellate cells, where it is expressed at high levels [117]. In normal liver, Gal-1 expression is mainly observed in endothelial cells, lymphocytes, and hepatocytes around the central vein [118]. It has been reported that Gal-1 expression is induced during liver regeneration [118].

Gal-3 expression is low in normal hepatocytes, but increases in cirrhosis and hepatocellular carcinoma [101]. It has been shown that Gal-3 expression is increased during liver inflammation and fibrosis [119]. Gal-3 plays a role in promoting hepatic stellate cell activation and proliferation [120].

Gal-9 is highly expressed in the liver, especially in Kupffer cells [121,122]. It plays an important role in maintaining immune homeostasis in the liver [121]. In liver tissue from patients with acute liver failure, Gal-9 has been reported to be localized in regenerating areas and colocalized with Kupffer cells. Kupffer cells play an important role in hepatic immunoregulation [123]. Kupffer cells function as a bridge between innate and adaptive immunity through the production of Gal-9 [123].

6. Liver Fibrosis

Understanding liver fibrosis is important because progression of liver fibrosis gradually reduces liver function and may ultimately lead to liver failure. Gal-3 plays a central role in the progression of liver fibrosis. Gal-3 is secreted by activated hepatic stellate cells and inflammatory macrophages and promotes fibroblast activation [124]. Gal-3 also plays a role in promoting the activation and proliferation of hepatic stellate cells [125]. Gal-3 promotes the phagocytosis of apoptotic cells by hepatic stellate cells through interaction with integrin αvβ3 [125]. The phagocytosis of apoptotic cells induces the transformation of hepatic stellate cells into myofibroblasts, collagen I production, and TGF-β production [125,126]. TGF-β requires intracellular Gal-3 to activate myofibroblasts and generate procollagen. Excessive deposition of extracellular matrix molecules and collagen by activated HSCs leads to altered tissue architecture, further damage, and ultimately organ failure through the formation of fibrous ridges and bridging fibrosis [126] (Figure 2).

7. Galectins and the Gut-Liver Axis

Galectins play important functions in both the gut and liver, and it has been suggested that they play a central role in interactions mediated by the gut-liver axis. In particular, Gal-1, -2, -3, -4, and -9 are expressed in the intestinal tract, each of which has different functions [127,128]. Gal-1 is mainly present in the lamina propria mucosal and suppresses excessive immune responses by promoting the induction of regulatory T cells and the apoptosis of inflammatory T cells [127]. Gal-3 is highly expressed in intestinal epithelial cells and is involved in interactions with intestinal bacteria and maintaining intestinal barrier function [128]. When the intestinal barrier function is disrupted and substances derived from intestinal bacteria enter the liver via the portal vein, inflammation and fibrosis of the liver are promoted. Galectins are involved in this process [129]. Alterations in the gut microbiota may affect the gut barrier function and the inflammatory state of the liver via galectins. Abnormal expression of galectins has been reported in pathologies such as nonalcoholic fatty liver disease [130].

8. Galectins and Liver Diseases

8.1. Chronic Hepatitis B (CHB)

Monocytes expressing Gal-9+ and PD-L1+ were significantly increased in patients with HBeAg-positive and HBeAg-negative CHB compared to healthy controls [131]. In CHB, the synergistic effect of high HBsAg concentrations with elevated TNF-α, IL-4, and IL-1β conveyed pleiotropic effects not only by upregulating both Gal-9 and PD-L1 on monocytes—leading to Gal-9-dependent immunological changes—but also by severely compromising the host immune response through PD-L1-induced attenuation of antiviral cytokine release by HBV-specific T/B cells and NK cells [131]. Monocytic Gal-9 and PD-L1 are heterogeneously expressed during different phases of CHB and exert diverse inhibitory effects on immune responses. Their therapeutic targeting may enhance anti-hepatitis B virus immunity (Table 1).

In HBV-related HCC, positive Gal-9 expression was associated with lymph node metastasis, a high Ki-67 proliferation index, and poor prognosis. Univariate and multivariate analyses demonstrated that Gal-9 expression can be used as an independent prognostic marker for HBV-related HCC [132,133]. The interaction between Tim-3 on Th1 and its ligand Gal-9 negatively regulates Th1-mediated immune responses. We showed that the Tim-3/Gal-9 signaling pathway mediates T cell senescence in HBV-associated HCC. [134]

Gal-3, through its interaction with macrophages, can stimulate cytokine and chemokine production via CD98 [135]. It plays an important role in the maintenance of HBV replication and may contribute to the pathological processes that lead to chronic HBV infection. Furthermore, Gal-3 can stimulate fibrogenesis by decreasing IL-10 production [136,137,138].

8.2. Hepatitis C Virus (HCV) Infection

Gal-9 and other members of the galectin family are widely implicated in viral infections, though their exact roles remain unclear [139]. Gal-9 expression has been observed in hepatocytes and Kupffer cells from liver biopsies of patients with hepatitis C virus (HCV) infection [140]. The levels of circulating Gal-9 and its expression in the serum of patients with HCV showed a positive correlation with the persistence of HCV infection and the progression of chronic liver disease [141]. The secretion of Gal-9 is promoted by IFN-α, which subsequently inhibits HCV infection [142].

HCV-positive patients exhibit significantly higher Gal-3 levels than HCV-negative patients [143]. However, Gal-3 levels in the serum of patients with HCV show no correlation with viral load, viral genotype, CRP, white blood cell count, or end-stage liver disease scores [144].

8.3. Metabolic Dysfunction-Associated Steatotic Liver Disease/Steatohepatitis (MASLD/MASH)

NOD-like receptor protein 3 (NLRP3) is a key molecule in inflammation research and its activation determines the course of various inflammatory diseases. Gal-3 can activate the NLRP3 inflammasome via toll-like receptor 4 (TLR4), promoting inflammatory responses in hepatocytes. The CRD of Gal-3 plays a regulatory role in the TLR4/NLRP3 pro-inflammatory pathway, which is involved in the initiation of lipid imbalance and inflammation in the liver [145].

In addition to NK cell markers, there is a subset of cells with a distinct immunological phenotype, characterized by the expression of invariant TCRs (Vα14-Jα18 in mice and Vα24-Jα18 in humans). These cells are known as NKT cells [146,147]. In the liver, Tim-3+ NKT cells are activated, and Gal-9 directly induces their apoptosis, contributing to NKT cell depletion during diet-induced steatosis. Gal-9 also interacts with Kupffer cells expressing Tim-3 to induce the secretion of IL-15 and promote NKT cell proliferation. Exogenous administration of Gal-9 significantly improves diet-induced steatosis by modulating NKT cell function in the liver. In summary, the Tim-3/Gal-9 signaling pathway plays an important role in maintaining hepatic NKT cell homeostasis by mediating activation-induced apoptosis and secondary proliferation, thereby contributing to the pathogenesis of MASH [148].

8.4. Alcohol Associated Liver Disease (ALD)

Patients with ALD, particularly those with a progressive form of the disease, exhibit significantly elevated supraphysiological plasma levels of soluble Tim-3 and its soluble ligand Gal-9 [149]. This elevation is associated with increased levels of soluble Tim-3 ligands and membrane-bound Tim-3 expression on immune cells. Soluble Tim-3 can block Tim-3-ligand synapses and improve antimicrobial immunity; however, the elevated levels of soluble Tim-3-binding ligands in patients with ALD counteract this immunostimulatory effect [149].

8.5. Autoimmune Hepatitis (AIH)

AIH, histologically referred to as interfacial hepatitis, is a progressive inflammatory liver disease characterized by hypergammaglobulinemia, circulating autoantibodies, and flamboyant mononuclear cell infiltration [150]. CD4 effector lymphocytes are the main orchestrators of liver injury in AIH, with their proliferation and pro-inflammatory cytokine secretion (e.g., interferon γ [IFNγ]) correlating with the activity and severity of liver disease [151]. In AIH, the degree of autoreactive CD4 T cell effector immune response is associated with the numerical and functional impairment of CD4 [152]. Gal-9 is a β-galactosidase-binding protein expressed by T-regs, and it plays a key role in their function. It inhibits Th1 immune response by binding to Tim-3 on CD4 effector cells. Reduced levels of Tim-3 in CD4(pos) CD25(neg) effector cells and Gal-9 in T-regs impair immunoregulation in AIH by rendering effector cells less prone to T-reg control and T-regs less capable of suppression [152].

8.6. Primary Biliary Cholangitis (PBC)

PBC is a chronic, inflammatory, autoimmune liver disease characterized by destructive lymphocytic inflammation of the small bile ducts in the liver, increased serum levels of antimitochondrial antibodies (AMAs) specific to mitochondrial autoantigens, and a high prevalence among females [153]. Gal-3 plays an inflammatory role in PBC due to its direct interaction with NLRP3 and its stimulation of inflammasome activation in hepatic macrophages. Activated inflammasomes in liver macrophages induce the production of pro-inflammatory cytokines, which affect the integrity of biliary epithelial cells and cause damage [154]. Consequently, the expression of Gal-3 in biliary epithelial cells increases during PBC, with these cells playing an active role in the pathogenesis of PBC.

8.7. Hepatocellular Carcinoma and Galectins

Gal-3 is not expressed in normal hepatocytes, whereas it is abundantly expressed in cirrhotic liver cancer and hepatocellular carcinoma. This suggests that Gal-3 may be involved in the formation of cirrhosis and hepatocellular carcinoma [155]. Correlation analysis of Gal-3 expression and microvessel density showed that Gal-3 expression in tumour cells promotes angiogenesis. The observed regulation of cell apoptosis was accompanied by Gal-3-mediated regulation of the caspase-3 signalling pathway in HCC cells [156]. Gal-3 inhibits tumor-reactive T cells and promotes tumor growth in mice receiving tumor-reactive T cells [157].

Urokinase plasminogen activator receptor (uPAR) is increased in many human cancers and is frequently associated with poor prognosis [158]. Silencing Gal-3 could significantly reduce the mRNA and protein levels of uPAR and its downstream signaling pathway in HCC cells by inhibiting the MEK/ERK signaling pathway. This inhibition may further affect the proliferation, migration, and invasion of HCC cells [159] (Figure 3).

Gal-9 can inhibit the proliferation of HCC cell lines by inducing cell apoptosis [160]. Additionally, Gal-9 increases the number of Tim-3-expressing DCs and CD8+ T cells, thereby enhancing anti-tumor immunity through its interaction with Tim-3 [134]. Typical Gal-9 receptors, such as T-cell immunoglobulin and Tim-3, are not expressed on the surface of HCC cell lines. Gal-9-induced apoptosis is inhibited by lactose administration, suggesting that this receptor should be glycosylated by β-galactoside [161]. In addition, interferon induces the expression of Gal-9 in HCC cells. The hyperexpression of Gal-9 in HCC cells induced by interferon is linked to the fact that Gal-9 is a target of microRNA 22 (miR-22), and its antitumor effect is enhanced by restoring Gal-9 expression in cells overexpressing miR-22 [162].

Gal-1 expression is elevated in HCC and increases further as the tumor progresses to advanced stages [163]. Gal-1 has been shown to interact with mRNA that preferentially binds to obstructive codons, thereby regulating angiogenesis [164]. Epithelial-mesenchymal transition (EMT) is well known to play a pivotal role in the seeding of malignant hepatocytes during HCC progression; Gal-1 overexpression promotes HCC progression by inducing HCC cell EMT via PI3K/AKT cascade activation [165,166,167].

9. Application to Liver Disease Diagnosis

9.1. Liver Fibrosis Screening

It has been reported that serum Gal-9 levels increase with the progression of liver fibrosis. An increase in serum Gal-9 concentration of 10 pg/mL was shown to be associated with a 3.90-fold increased odds of progression to liver fibrosis. [168]. Therefore, serum Gal-9 levels are expected to be a potential biomarker for liver fibrosis in patients with chronic liver disease.

Elevated Gal-3 levels in liver biopsies can be used to distinguish F3/F4 from F0/F1 fibrotic stages [169]. Furthermore, Gal-3 is associated with fibrotic zones in the liver [170].

9.2. Early Detection and Prognosis of HCC

Serum Gal-3 levels were significantly higher in patients with HCC compared with healthy controls (mean difference = 3.06, 95% CI = 1.79–4.32, p < 0.001) [171]. High expression of Gal-1 and -3 in tissues of HCC patients has been shown to be associated with poor overall survival (Gal-1: HR = 1.94, 95% CI = 1.61–2.34, p < 0.001; Gal-3: HR = 3.29, 95% CI = 1.62–6.68, p < 0.001). On the other hand, high expression of Gal-4 and -9 has been reported to be associated with favorable overall survival in HCC patients (Gal-4: HR = 0.53, 95% CI = 0.36–0.79, p = 0.002; Gal-9: HR = 0.56, 95% CI = 0.44–0.71, p < 0.001)3 [171].

9.3. Early Diagnosis of Acute Liver Damage

Detecting a sudden increase in serum Gal-3 levels may be useful for early diagnosis and severity evaluation of acute liver damage [172]. Gal-3 is expressed on NKT cells in the liver and is involved in dendritic cell interactions, playing an important pro-inflammatory role in acute liver injury [173].

10. Conclusions

Galectins are a family of proteins with significant potential in the medical field. Therapies targeting galectins are emerging as promising approaches for treating many diseases, including cancer, fibrosis, and cardiovascular conditions. Galectins are gaining prominence as diagnostic biomarkers, potentially contributing to early diagnosis and the advancement of personalized medicine. In the field of the liver, it may be possible to use time-dependent changes in serum galectin levels to assess the effectiveness of antiviral therapy and liver fibrosis treatment. In addition, serum galectin levels may be used to stratify the risk of disease progression in patients with chronic liver disease, allowing for more appropriate management and follow-up plans. These applications are expected to enable early detection and early intervention of liver diseases, leading to improved prognosis for patients. However, before diagnostic tools using galectins can be put to practical use, validation through large-scale prospective studies, standardization of measurement methods, optimization of cutoff values, etc. are required. While galectins have many interesting functions in terms of cell and molecular biology, the functions and mechanisms of galectins are complex and still unknown. Since the expression patterns of galectins differ across tissues, targeting galectins overexpressed in specific tissues may improve tissue selectivity. These features highlight the growing importance of galectin-targeted therapeutics, given their high selectivity and versatile roles across various applications. The medical applications of galectins are rapidly progressing from basic research to clinical applications, with further development expected in the future.