Pleiotropic regulatory mechanisms and targeted therapeutic prospects of Galectin-3 in aging-related diseases

Abstract

Aging is a major risk factor for numerous chronic diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), atherosclerosis (AS), type 2 diabetes mellitus (T2DM), osteoarthritis (OA) and age-related macular degeneration (AMD). Galectin-3 (Gal-3), a unique β-galactoside-binding lectin, has emerged as a critical mediator in the pathogenesis of AD and other age-related disorders by modulating key mechanisms such as inflammation, oxidative stress, and apoptosis. While emphasizing neurological disorders (AD, PD), this review also examines Gal-3's role in systemic age-related conditions (T2DM, AS, OA, AMD) that frequently co-occur with or influence neurodegeneration. This review summarizes current knowledge on the expression patterns, molecular mechanisms, and therapeutic potential of Gal-3 in aging-related diseases. Elevated Gal-3 levels have been detected in the brain tissue and cerebrospinal fluid of AD patients, where it contributes to multiple pathological processes, including microglia-driven neuroinflammation, Aβ plaque deposition, tau hyperphosphorylation, oxidative damage, and neuronal apoptosis. Furthermore, Gal-3 upregulation is observed across various age-related diseases and correlates with disease progression, underscoring its potential as a diagnostic biomarker and therapeutic target. Preclinical studies demonstrate that Gal-3-targeted interventions—including small-molecule inhibitors (e.g., TD-139), natural compounds (e.g., modified citrus pectin), and other pharmacological agents—exert neuroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects by binding to Gal-3 and modulating its activity in animal models, offering promising avenues for multi-disease treatment. However, the dual roles and complex regulatory networks of Gal-3 present challenges for clinical translation, requiring context-specific therapeutic approaches tailored to distinct disease mechanisms. Future research should focus on elucidating tissue-specific mechanisms and optimizing combination therapies to enable precise targeting of aging-related pathologies.

Graphical abstract

Introduction

Aging is a progressive biological process characterized by physiological decline and functional impairment across tissues and organs, representing the primary risk factor for most chronic human diseases [1]. Currently, it is believed that the factors leading to aging mainly include DNA damage, telomere shortening, chronic inflammation, epigenetic dysregulation, reactive oxygen species (ROS) accumulation, protein homeostasis imbalance and mitochondrial dysfunction [2]. These interconnected mechanisms drive the pathogenesis of age-related disorders, including neurodegenerative diseases (e.g., Alzheimer's disease [AD], Parkinson's disease [PD]), metabolic disorders (e.g., type 2 diabetes mellitus [T2DM]), cardiovascular diseases (e.g., atherosclerosis [AS]), age-related macular degeneration (AMD), and osteoarthritis (OA) [[3], [4], [5], [6], [7], [8]]. Shared pathological features such as oxidative stress, chronic inflammation, autophagy dysfunction, and aberrant apoptosis further link these conditions [9]. Among age-related diseases, AD—a progressive neurodegenerative disorder marked by cognitive decline—exemplifies the central role of aging in disease etiology [10,11]. Its prevalence escalates with age, affecting approximately 10 ​% of individuals aged ≥65 years [12]. Notably, epidemiological and mechanistic studies reveal bidirectional comorbidities between AD and other aging-related diseases, including T2DM and AS, suggesting overlapping pathological networks [13]. For instance, oxidative stress and neuroinflammation, key drivers of AD, are exacerbated by T2DM-related insulin resistance (IR) and chronic hyperglycemia, which promote neuronal damage [14,15]. Moreover, mitochondrial dyshomeostasis, a core aging feature, links AD pathology (e.g., amyloid-β deposition) and AS via defective mitophagy, impaired oxidative phosphorylation, and mitochondrial DNA leakage [16]. Despite advances in understanding these interconnections, the precise molecular mechanisms and temporal dynamics underlying disease relationships remain elusive. Addressing these knowledge gaps is critical for developing interventions to mitigate aging-associated morbidity and reduce the global burden of age-related diseases.

Biological functions of Galectin-3 (Gal-3)

The Galectin family comprises a group of endogenous glycan-binding proteins that are ubiquitously expressed across a variety of organisms [17]. These proteins are primarily synthesized in the cytoplasm and are characterized by their ability to specifically recognize and bind β-galactoside-containing glycans through an evolutionarily conserved carbohydrate recognition domain (CRD) [18]. Through this molecular interaction, galectins modulate diverse pathophysiological processes, including inflammatory responses, immune regulation, and cellular proliferation [19,20]. To date, fifteen Galectin family members have been identified, which are classified according to their structural features: (1) proto-typic Galectin: including Galectin-1, 2, 5, 7, 10, 11, 13, 14, and 15, which is characterized by a single CRD and a dimerization function; (2) tandem-repeat Galectin: including Galectin-4, 6, 8, 9, and 12, which are characterized by containing two distinct CRDs within a single polypeptide chain and oligomerization; and (3) unique chimeric-type Galectin: Gal-3, the sole family member featuring an N-terminal collagen-like domain that facilitates oligomerization and a C-terminal CRD that mediates carbohydrate binding [21,22]. Gal-3 exhibits broad tissue distribution, with particularly high expression in immune cells (macrophages, mast cells, neutrophils) as well as epithelial and endothelial cells. Its pleiotropic functions encompass modulation of inflammatory responses, apoptosis, fibrotic processes, and neurodegenerative pathways [23,24]. Fig. 1 illustrates the structural classification of the galectin family with emphasis on the unique architecture of Gal-3. Within the central nervous system (CNS), Gal-3 expression is predominantly localized to microglia and astrocytes. Activated microglia, through their secretion of various inflammatory mediators, serve as pivotal regulators of chronic neuroinflammation [25,26]. Emerging evidence positions Gal-3 as a critical modulator of microglial activation and neuroinflammatory responses in neurodegenerative disorders [27]. Recent advances have highlighted Gal-3's significant role in aging-related pathologies [28]. Notably, Gal-3 expression demonstrates a marked age-dependent increase, suggesting its potential utility as an early biomarker for senescence-associated diseases [29]. In AD, Gal-3 promotes microglial activation and alters the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio, indicating its involvement in both inflammatory and apoptotic pathways [30]. Similarly, in OA, Gal-3 contributes to disease progression by disrupting the equilibrium between bone formation and resorption, while also influencing vascular smooth muscle cell (VSMC) calcification through autophagy and inflammatory mechanisms [31]. Under conditions of T2DM, Gal-3 exacerbates oxidative stress by promoting lipid peroxidation, as evidenced by increased malondialdehyde (MDA) levels and decreased superoxide dismutase (SOD) activity, ultimately accelerating cellular senescence [32]. These findings collectively support the hypothesis that elevated Gal-3 expression may represent a common pathogenic link among various age-associated conditions, including cardiovascular diseases, T2DM, and OA. Given its structural uniqueness and functional versatility, Gal-3 has emerged as a promising therapeutic target for aging-related diseases. A comprehensive understanding of Gal-3's biological functions and regulatory mechanisms may pave the way for novel preventive and therapeutic strategies against these conditions. This review systematically examines the multidimensional regulatory mechanisms of Gal-3 and explores its potential as a therapeutic target in aging-related diseases.

Fig. 1.

The galectin family is structurally classified into three subtypes (1) proto-type galectins (e.g., Gal-1, -2, -5, -7): containing a single conserved CRD (green) that mediates dimerization; (2) tandem-repeat galectins (e.g., Gal-4, -6, -8, -9, -12); featuring two distinct CRDs within one polypeptide chain - an N-terminal CRD (blue) and a C-terminal CRD (purple) - connected by a linker peptide, with differential ligand-binding affinities and oligomerization properties; and (3) the unique chimeric-type galectin (Gal-3 exclusively) comprising an NTD, CLS, and C-terminal CRD (yellow) that enables pentamer formation. (Abbreviations: Gal, galectin; CRD, carbohydrate recognition domain; NTD, N-terminal domain; CLS, collagen-like sequence.)

The role and mechanism of Gal-3 in AD

AD represents the most prevalent age-related neurodegenerative disorder, responsible for 60–70 ​% of dementia cases in elderly populations [33]. Aging, as the primary independent risk factor for AD, exhibits intrinsic mechanistic links to age-associated metabolic dysregulation, oxidative stress, and immune dysfunction [34]. The hallmark neuropathological features of AD include senile plaques resulting from aberrant β-amyloid (Aβ) deposition, neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein aggregates, and progressive neuronal loss with synaptic dysfunction. These pathological processes collectively contribute to progressive cerebral impairment [12,35]. Emerging evidence demonstrates significant Gal-3 upregulation in hippocampal tissues of AD animal models [36]. Clinical observations parallel these findings, showing elevated Gal-3 expression in both serum and cerebrospinal fluid of AD patients, with levels correlating positively with disease severity [[36], [37], [38]] and pathological progression [38]. Recent research has established neuroinflammation as a critical driver of AD pathogenesis [39]. This inflammatory response exhibits a dual-phase nature-potentially protective during initial stages but progressively detrimental when dysregulated [40]. Additionally, Gal-3 may directly participate in the abnormal aggregation of Tau protein, oxidative stress, and pathological apoptosis processes [41]. These collective findings position Gal-3 not merely as a neuroinflammatory mediator, but as a multifactorial contributor to AD pathogenesis through diverse molecular mechanisms. Elucidating the pleiotropic roles of Gal-3 in AD may provide novel therapeutic avenues, potentially enabling the development of combined anti-inflammatory and disease-modifying treatment strategies that transcend conventional therapeutic approaches.

Gal-3 and microglial activation-mediated neuroinflammation in AD

Microglia, originating from primitive myeloid precursor cells in the embryonic yolk sac, represent the sole highly specialized tissue-resident macrophages within the CNS parenchyma [42]. Beyond their roles in immune surveillance and inflammatory regulation, these cells are critically involved in neurodevelopment, synaptic plasticity, and the pathogenesis of neurodegenerative disorders [43]. In response to diverse microenvironments, microglia can undergo polarization into distinct phenotypes: the pro-inflammatory “classically activated” (M1-type) and the anti-inflammatory “alternatively activated” (M2-type). This polarization dynamic has been implicated as a key functional response in various CNS pathologies [44]. Neuroinflammation serves as a double-edged sword in AD progression. During early disease stages, a controlled inflammatory response facilitates Aβ clearance, with microglia encapsulating Aβ plaques through TREM2-dependent phagocytosis, thereby limiting plaque dissemination [45]. However, sustained chronic neuroinflammation triggers M1-type microglia to release pro-inflammatory cytokines, culminating in neuronal apoptosis, synaptic degeneration, and cognitive impairment [46]. Consequently, neuroinflammatory dysregulation is now recognized as the third core pathological feature of AD, alongside Aβ deposition and tau hyperphosphorylation. Recent investigations by Boza-Serrano et al. revealed that Gal-3 functions as an endogenous TREM2 ligand, binding specifically to the glycosylated domain of TREM2 via its CRD to form a Gal-3-TREM2 complex. This interaction initiates the DNAX-activation protein 12 (DAP12) signaling cascade. The resultant Gal-3/TREM2/DAP12 axis potently activates microglia, exacerbating neuroinflammation through sustained cytokine release and ultimately accelerating AD pathogenesis [47]. Transcriptomic analyses demonstrated significant downregulation of toll-like receptor (TLR)-associated genes (including TLR2 and TLR9) in Gal-3-deficient 5xFAD mice, underscoring Gal-3's pivotal role in TLR-mediated signaling [47]. Complementary studies established that Gal-3 knockdown suppresses the TLR4/NF-κB pathway, attenuates hippocampal pro-inflammatory cytokine levels in lipopolysaccharide (LPS)-challenged aged mice, inhibits microglial activation, and rescues cognitive deficits [48]. In vitro experiments further confirmed that Gal-3 triggers microglial activation via TLR4, stimulating secretion of IL-6, IL-12, and TNF-α [47]. Additionally, Gal-3 engages cell surface receptors to activate the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. This signaling cascade modulates inflammatory gene expression, upregulating pro-inflammatory mediators (TNF-α, IL-12, IL-1β) and enhancing inducible nitric oxide synthase (iNOS) production [49].

The abnormal expression of Gal-3 promotes the deposition of Aβ and the hyperphosphorylation of tau protein

Aβ deposition represents one of the hallmark pathological features of AD. The generation of Aβ occurs through sequential proteolytic cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase, with subsequent aberrant aggregation forming neurotoxic oligomers and senile plaques [50]. Emerging evidence indicates that Gal-3 plays a multifaceted role in modulating Aβ generation, aggregation, and clearance, thereby exacerbating Aβ deposition [51,52]. In vitro studies have demonstrated that Gal-3 accelerates the conformational transition of Aβ from monomers to oligomers and fibrils through direct binding to β-sheet structures via its CRD. This process has been quantitatively assessed using thioflavin T fluorescence intensity measurements [47]. Furthermore, Gal-3 indirectly impairs Aβ clearance by promoting microglia-mediated neuroinflammation. In AD mouse models, Gal-3 expression is predominantly localized to microglia surrounding Aβ plaques, where it triggers the release of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) through interaction with the TREM2 receptor and subsequent activation of the DAP12/Syk signaling pathway [47]. This chronic inflammatory state not only compromises microglial phagocytic function but also downregulates neprilysin (NEP) expression [53], a zinc-dependent metalloproteinase critical for Aβ clearance [54]. Notably, NEP specifically degrades soluble Aβ monomers and inhibits their aggregation. Clinical observations reveal significantly reduced NEP expression and activity in AD brains, correlating with impaired Aβ clearance and accelerated deposition [55]. Genetic ablation of Gal-3 results in significant upregulation of NEP expression. Mechanistic investigations suggest this phenomenon involves enhanced cAMP response element-binding protein (CREB) binding activity within the NEP promoter region. Detailed pathway analysis reveals that Gal-3 likely modulates NEP expression through suppression of the integrin/FAK/CREB signaling axis [36]. Specifically, Gal-3 interferes with integrin-mediated FAK phosphorylation, thereby attenuating CREB transcriptional activity and its binding affinity for the NEP promoter [56]. Concurrently, Gal-3 has been shown to enhance BACE1 activity, increasing Aβ production. This dual regulatory mechanism-simultaneous suppression of Aβ-degrading NEP and promotion of Aβ-generating BACE1-creates a metabolic imbalance favoring Aβ accumulation, establishing a pathogenic positive feedback loop [36]. These findings provide novel insights into the molecular basis of Aβ dyshomeostasis in AD pathogenesis. Complementing these mechanisms, Qiu et al. demonstrated that Gal-3 activates the c-Jun N-terminal kinase (JNK) pathway, upregulating presenilin 1 (PS1) expression and consequently enhancing γ-secretase activity. This promotes APP processing and Aβ generation, facilitating oligomerization and plaque deposition [57]. Another study identified that Gal-3 impairs Aβ clearance through inhibition of the PI3K/AKT/mTOR pathway, further contributing to cerebral Aβ accumulation [58].

The hyperphosphorylation of Tau protein and subsequent formation of NFTs constitute another central pathological hallmark of AD [59]. Under physiological conditions, Tau stabilizes microtubules, but its aberrant hyperphosphorylation disrupts microtubule binding, leading to cytoskeletal destabilization and neuronal dysfunction [60]. The phosphorylation state of Tau is tightly regulated by a balance between kinases (e.g., GSK-3β, CDK5) and phosphatases (e.g., PP2A) [61]. However, in AD brains, this equilibrium is disrupted, with elevated GSK-3β activity and diminished PP2A function, resulting in pathological Tau phosphorylation at critical residues such as Ser396 and Ser404 [62]. Emerging evidence indicates that Gal-3 contributes to Tau pathology through multiple mechanisms. A structural study revealed that CRD of Gal-3 directly interacts with phosphorylated Tau, accelerating its conformational transition into β-sheet-rich structures and facilitating NFT assembly [63]. This interaction suggests that Gal-3 acts as a molecular scaffold, promoting Tau aggregation in a manner analogous to its role in Aβ oligomerization. Beyond direct aggregation, Gal-3 exacerbates Tau pathology by facilitating its interneuronal propagation. Low-density lipoprotein receptor-related protein 1 (LRP1), a key mediator of Tau internalization and axonal transport, has been implicated in the cell-to-cell transmission of pathogenic Tau species [64]. Boza-Serrano et al. demonstrated that Gal-3 amplifies LRP1-dependent Tau uptake and spreading, thereby accelerating the dissemination of Tau pathology across neural networks [41]. This finding underscores Gal-3's role in promoting the prion-like spread of Tau aggregates, a critical process in AD progression.

Gal-3 and oxidative stress and aberrant apoptosis in AD

Oxidative stress is defined by a pathological imbalance between the excessive production of ROS and the cellular antioxidant defense system [65]. In AD, the accumulation of Aβ plaques and hyperphosphorylated tau proteins induces mitochondrial dysfunction, resulting in excessive ROS generation. This oxidative burden promotes lipid peroxidation, protein oxidation, and DNA damage, contributing to neuronal degeneration [66,67]. Furthermore, neuroinflammation-driven microglial activation exacerbates oxidative stress through mechanisms involving nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [68]. Gal-3, a key mediator of inflammation and immune regulation, plays a multifaceted role in oxidative stress. Studies demonstrate that Gal-3 enhances ROS production by activating the TLR4/MyD88/NF-κB signaling pathway, thereby promoting the release of pro-inflammatory cytokines, including TNF-α and IL-6. Concurrently, Gal-3 impairs cellular antioxidant defenses by suppressing the activity of critical enzymes such as SOD. Notably, in AD animal models, Gal-3 knockdown significantly reduced hippocampal MDA levels—a marker of lipid peroxidation—while enhancing SOD activity, suggesting its pivotal role in modulating the oxidative-antioxidative equilibrium during AD pathogenesis [69].

Neuronal apoptosis plays a pivotal role in synaptic degeneration and cognitive impairment in AD, primarily mediated by the mitochondrial and death receptor pathways [70]. A key mechanism involves Aβ oligomers, which disrupt the balance of Bcl-2 family proteins—particularly by altering the Bax/Bcl-2 ratio—through caspase cascade activation. This imbalance leads to mitochondrial dysfunction, characterized by the loss of membrane potential (ΔΨm) and cytochrome C release, ultimately triggering apoptotic cell death [71]. Emerging evidence implicates Gal-3 in promoting neuronal apoptosis in AD via both direct and indirect mechanisms. Gal-3 interacts with Bcl-2 proteins, suppressing their anti-apoptotic activity while upregulating the pro-apoptotic protein Bax. Furthermore, in an LPS-induced AD mouse model, hippocampal Gal-3 knockdown significantly reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, downregulated cleaved caspase-3 levels, and restored the Bcl-2/Bax ratio. These findings suggest that Gal-3 actively contributes to neuronal death in AD by modulating key apoptotic signaling pathways [48] (Fig. 2).

Fig. 2.

The specific mechanisms of action and signaling pathways of Gal-3 across Alzheimer's disease.

The role and mechanism of Gal-3 in other aging-related diseases

Gal-3 and PD

PD, the second most prevalent neurodegenerative disorder after AD, is strongly associated with aging [72]. Clinically, PD manifests with progressive motor impairments—including bradykinesia, tremor, rigidity, and dyskinesia—as well as non-motor symptoms such as constipation, olfactory dysfunction, and sleep disturbances, which often emerge in early disease stages [73]. The neuropathological hallmarks of PD include the degeneration of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies and Lewy neurites, which are primarily composed of aggregated α-synuclein (α-syn) protofibrils [74]. α-Synuclein, a small soluble protein encoded by the SNCA gene, undergoes misfolding and aggregation under conditions such as aging, genetic predisposition, oxidative stress, or neuroinflammation [75]. These aggregates adopt Aβ-sheet-rich, insoluble conformation, forming toxic protofibrils that drive PD pathogenesis [76]. Emerging evidence highlights Gal-3 as a critical contributor to PD progression. Elevated serum Gal-3 levels correlate with disease severity, suggesting its potential as a biomarker for monitoring PD progression. Notably, patients with idiopathic PD (IPD) exhibit significantly higher serum Gal-3 concentrations than healthy controls, with further increases observed as the disease advances [77]. Longitudinal studies reinforce this association, demonstrating that Gal-3 levels not only rise with age but also correlate positively with motor dysfunction severity, as assessed by the Unified PD Rating Scale (UPDRS) [78]. Mechanistically, Gal-3 participates in PD pathogenesis through multiple pathways. Gal-3 promotes aberrant α-syn secretion via lysosomal dysfunction. Upon lysosomal damage, Gal-3 recruits TRIM16 and ATG16L1 to form a complex that activates an autophagy-dependent non-classical secretion pathway, facilitating the extracellular release of α-syn and subsequent neuronal damage [79]. Second, Gal-3 interacts with α-synuclein protofibrils, destabilizing their secondary structure and fragmenting long fibrils into shorter, more toxic strains. These truncated aggregates exhibit enhanced membrane permeability, disrupting mitochondrial function and exacerbating oxidative stress [80]. In addition, Gal-3 exacerbates neuroinflammation by binding to TLR4 or promoting NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly, thereby activating the NF-κB pathway and upregulating pro-inflammatory cytokines such as IL-1β and TNF-α [81]. Collectively, these findings position Gal-3 as a central regulator of PD neurodegeneration, influencing α-synuclein dynamics, lysosomal-autophagic dysfunction, and neuroinflammatory cascades (Fig. 3). Targeting Gal-3 may thus represent a promising therapeutic strategy for modifying PD progression.

Fig. 3.

The specific mechanisms of action and signaling pathways of Gal-3 across Parkinson's disease.

Gal-3 and T2DM

DM has emerged as one of the most significant global public health challenges of the 21st century, with its prevalence continuing to rise at an alarming rate [82]. Current projections from the International Diabetes Federation estimate that the global diabetic population will reach 783 million by 2045, representing a prevalence exceeding 12.2 ​% [83]. Clinically categorized into type 1 diabetes (T1DM) and T2DM, the latter accounts for over 90 ​% of all DM cases [84]. T2DM is characterized by chronic hyperglycemia resulting from two primary pathophysiological mechanisms: IR and pancreatic β-cell dysfunction [85]. IR manifests as diminished tissue responsiveness to insulin, impairing glucose and lipid homeostasis [86]. In insulin-target tissues (muscle, adipose, and liver), this resistance leads to reduced glucose uptake and utilization, enhanced lipolysis, and elevated circulating free fatty acids-collectively exacerbating metabolic dysregulation [87]. Compensatory β-cell hyperplasia and hyperinsulinemia initially counteract IR, but chronic exposure to glucotoxicity, lipotoxicity, and inflammatory mediators (e.g., IL-1β) ultimately precipitates β-cell apoptosis [88]. Clinical investigations have demonstrated significantly elevated serum Gal-3 levels in both prediabetic and T2DM populations compared to healthy controls, with strong correlations observed with fasting plasma glucose, 2-h postprandial glucose, and HOMA-IR scores [89]. Cross-sectional studies further reveal upregulated Gal-3 expression in both serum and pancreatic β-cells of T2DM patients, showing positive correlations with IR severity and degree of β-cell dysfunction [90]. Pathological analyses identify increased Gal-3 expression in glomeruli and tubular interstitium of diabetic kidney disease (DKD) patients, with levels correlating with renal fibrosis progression [91], while adipose tissue macrophages in obese T2DM patients exhibit enhanced Gal-3 secretion [92,93].

Gal-3 contributes to T2DM pathogenesis through multiple interconnected mechanisms. First, as a potent pro-inflammatory mediator, Gal-3 establishes a vicious cycle of chronic low-grade inflammation and IR. Molecular studies demonstrate that Gal-3 binding to TLR4 activates the MyD88-dependent signaling cascade, inducing NF-κB nuclear translocation and subsequent release of pro-inflammatory cytokines including TNF-α and IL-6 [90]. This inflammatory response markedly increases F4/80⁺ macrophage infiltration in adipose tissue, exacerbating islet inflammation and promoting IR progression. Importantly, Gal-3 drives macrophage polarization toward the pro-inflammatory M1 phenotype while suppressing M2 transformation via modulation of the mTOR/S6/4E-BP1 signaling axis, resulting in pathological elevation of IL-1β within pancreatic islets that directly triggers β-cell apoptosis [94]. Additionally, Gal-3-mediated M1 polarization promotes sustained release of inflammatory cytokines (TNF-α, IL-1β), further impairing β-cell function and exacerbating IR [92]. Second, Gal-3 significantly contributes to oxidative stress in T2DM by increasing ROS and MDA production while reducing antioxidant defenses, leading to β-cell dysfunction and apoptosis through oxidative damage [95,96]. Third, Gal-3 activates mitochondrial apoptosis via Bax upregulation and Bcl-2 downregulation, directly inducing β-cell death [90]. In addition, extracellular Gal-3 binds insulin receptor β-subunits, inhibiting tyrosine phosphorylation and disrupting IRS1/PI3K/AKT signaling, while concurrently impairing GLUT4 membrane translocation in muscle and adipose tissue, thereby compromising both insulin signaling and glucose uptake [97]. Regarding insulin secretion, Gal-3 disrupts calcium signaling through the CACNG1/L-VGCCs axis, directly impairing β-cell function [98]. Finally, Gal-3 serves as a key advanced glycation end products (AGEs)/ALEs ligand, forming a pathogenic feedback loop with RAGE that exacerbates diabetic complications through sustained inflammation, IR, and β-cell dysfunction [99] (Fig. 4). Collectively, these findings position Gal-3 as a central regulator in T2DM pathogenesis and progression, offering promising therapeutic potential for targeted interventions.

Fig. 4.

The specific mechanisms of action and signaling pathways of Gal-3 across type 2 diabetes.

Gal-3 and AS

AS represents a group of chronic inflammatory vascular diseases characterized by lipid deposition, endothelial dysfunction, macrophage infiltration, and fibrous plaque formation, ultimately leading to cardiovascular events through arterial lumen narrowing or plaque rupture [100,101]. As the primary pathological basis of cardiovascular diseases, AS-related fatalities account for 33 ​% of global mortality (approximately 17.9 million deaths in 2021), with prevalence markedly increasing with age, suggesting a strong association with the aging process [102]. The pathophysiological mechanisms of AS involve complex inflammatory responses, oxidative stress, and aberrant cell signaling pathways [103,104]. Recent studies have highlighted the critical role of Gal-3 in AS pathogenesis. Elevated Gal-3 expression has been detected in both serum and atherosclerotic plaques of AS patients, exhibiting a positive correlation with plaque instability and disease severity [105]. Animal studies further demonstrate that Gal-3 knockout mice exhibit significantly reduced arterial plaque areas and lower inflammatory cytokine levels, confirming Gal-3 as a key regulatory molecule in AS progression [106]. Endothelial dysfunction serves as the initiating factor in AS development, contributing to inflammatory responses, vascular injury, and plaque formation [107]. Gal-3 plays a pivotal role in oxidized low-density lipoprotein (ox-LDL)-induced endothelial dysfunction by upregulating lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression and enhancing NADPH oxidase activity, resulting in excessive ROS generation. This oxidative stress subsequently activates p38 MAPK and NF-κB pathways, promoting inflammation and endothelial impairment [108]. Additionally, Gal-3 exacerbates inflammatory responses and endothelial damage by activating the integrin β1/RhoA/JNK signaling pathway, which stimulates the NF-κB inflammatory cascade, upregulating pro-inflammatory cytokines (IL-6, IL-8) and adhesion molecules (VCAM-1) [105]. Gal-3 overexpression also enhances NF-κB-mediated TFEB nuclear translocation, augmenting autophagy and further amplifying the inflammatory response [109]. Under physiological conditions, VSMCs reside in the arterial medial layer, regulating blood pressure and flow [110]. However, under pathological stimuli, VSMCs undergo phenotypic switching, characterized by increased proliferation, migration, and excessive extracellular matrix (ECM) and cytokine secretion, driving AS progression [111]. Gal-3 promotes VSMC osteogenic differentiation and calcification by stabilizing β-catenin and activating the Wnt pathway [112]. Furthermore, Gal-3 modulates MAPK/FAK phosphorylation through ERK/p38 MAPK and Src/FAK signaling pathways, enhancing VSMC migration and increasing plaque rupture risk [113]. During AS development, macrophages internalize ox-LDL via scavenger receptors (e.g., SR-A, CD36), leading to intracellular lipid accumulation and foam cell formation [114]. Foam cell deposition in the arterial subendothelium constitutes a critical step in atherosclerotic plaque initiation [115]. In ApoE-deficient mouse models, Gal-3 is predominantly localized in plaque macrophages and endothelial cells, with expression levels escalating in response to high-fat diet-induced plaque progression [116]. Zhu et al. demonstrated that Gal-3 overexpression promotes monocyte-to-macrophage differentiation and enhances ox-LDL uptake, accelerating foam cell formation [117] (Fig. 5).

Fig. 5.

The specific mechanisms of action and signaling pathways of Gal-3 across atherosclerosis.

Gal-3 and OA

OA is a prevalent age-related degenerative joint disorder characterized by articular cartilage degradation, subchondral bone sclerosis, synovial inflammation, and osteophyte formation. Globally, OA affects over 30 ​% of individuals aged 65 years or older [118], with epidemiological data demonstrating a rising incidence that positions OA as a leading cause of adult disability worldwide [119]. The pathogenesis of OA involves multifactorial mechanisms including mechanical stress, metabolic dysregulation, and chronic low-grade inflammation, with aberrant activation of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and matrix metalloproteinases (MMPs) constituting central drivers of ECM degradation [120]. Emerging evidence implicates Gal-3 in multiple OA-related pathological processes through its regulation of osteoclast and osteoblast activities, including apoptosis, inflammatory responses, and cellular proliferation [121,122]. Immunohistochemical and RT-PCR analyses reveal that Gal-3 expression in OA cartilage is markedly elevated compared to normal tissues, with pronounced localization in severely degenerated regions [123]. Notably, Gal-3 concentrations in synovial fluid significantly exceed plasma levels and exhibit a strong positive correlation with radiographic disease severity (Kellgren-Lawrence grade), suggesting its potential as a biomarker for OA progression [124]. At the molecular level, Gal-3 demonstrates cytoplasmic-membrane dual localization in chondrocytes, where it disrupts cartilage homeostasis via integrin β1-mediated mechanotransduction pathways. Furthermore, Gal-3 undergoes specific cleavage by collagenase-3 (MMP-13), resulting in conformational changes to its ligand-binding domain and establishing a positive feedback loop that exacerbates ECM degradation [125].

The mechanistic involvement of Gal-3 in OA pathogenesis encompasses three major aspects: chondrocyte apoptosis, inflammatory cascades, and ECM metabolic imbalance. In vitro studies using the TC28a2 human chondrocyte model demonstrate that Gal-3 activates the NADPH oxidase complex (NOX-2/p22phox/p47phox) through TLR4/MyD88-dependent signaling, triggering ROS overproduction and subsequent ERK/NF-κB pathway activation, which promotes secretion of pro-inflammatory cytokines (IL-6, IL-8). Concurrently, Gal-3 induces mitochondrial dysfunction via PGC-1α downregulation, activating the Bax/cytochrome C-dependent apoptotic pathway [122]. Additionally, Gal-3 suppresses anabolic gene expression (aggrecan, SOX9) through PI3K/Akt inhibition while upregulating catabolic enzymes (MMP-13, ADAMTS-5) [124]. In LPS-stimulated ATDC5 cells, Gal-3 inhibition attenuates inflammatory damage by suppressing NF-κB activation, leading to decreased production of inflammatory mediators (IL-1β, IL-6, TNF-α, NO, PGE2) and downregulation of MMP expression [121] (Fig. 6). These findings collectively position Gal-3 as a promising diagnostic biomarker and therapeutic target for OA intervention.

Fig. 6.

The specific mechanisms of action and signaling pathways of Gal-3 across osteoarthritis.

Gal-3 and AMD

AMD represents a progressive neurodegenerative disorder affecting the macular region of the retina, standing as the predominant cause of irreversible vision loss among elderly populations in developed nations [126]. With a global prevalence of 8.7 ​% in individuals over 45 years, AMD cases are projected to reach 284 million by 2040, presenting significant public health challenges due to its high potential for blindness induction [127]. The disease primarily targets the retinal pigment epithelium (RPE), Bruch's membrane, photoreceptors, and choroid, resulting in permanent visual impairment [128]. Pathologically, AMD is characterized by drusen formation-extracellular protein and lipid deposits accumulating between the RPE layer and Bruch's membrane [129]. Late-stage AMD manifests as either dry AMD (geographic atrophy, GA) or wet AMD (choroidal neovascularization, CNV), with GA accounting for 80–90 ​% of cases and currently lacking effective treatments [130]. Chronic inflammation and oxidative stress constitute fundamental pathological mechanisms driving AMD progression [131].

Clinical investigations have demonstrated significant upregulation of Gal-3 expression in AMD patient RPE cells, with both mRNA and protein levels markedly elevated compared to healthy controls [132]. The expression intensity of Gal-3 shows positive correlation with drusen volume, while elevated serum Gal-3 levels associate with increased macular thickness, suggesting its potential as a biomarker for disease progression [133]. Mechanistically, Gal-3 contributes to AMD pathogenesis through multiple pathways. By binding ECM components such as fibronectin, Gal-3 promotes abnormal RPE cell-matrix adhesion and accelerates protein aggregation, facilitating drusen core formation [134]. Furthermore, Gal-3 interaction with advanced glycation end-products (AGEs) contributes to Bruch's membrane thickening and RPE dysfunction [132]. Through JAK/STAT pathway activation, Gal-3 stimulates microglia to produce pro-inflammatory cytokines (IL-1β, CCL2), exacerbating retinal chronic inflammation [135]. Intriguingly, Gal-3 exhibits dual functionality-its binding to TREM2 receptors can enhance microglial phagocytic capacity, suggesting context-dependent neuroprotective effects [136]. In wet AMD pathogenesis, Gal-3 promotes CNV development through two distinct mechanisms. Under hypoxic conditions, HIF-1α binds to hypoxia response elements (HREs) in the Gal-3 promoter region, creating a vicious cycle of angiogenic stimulation [137]. Concurrently, Gal-3 interacts with integrin αvβ3 FAK to facilitate endothelial cell migration while inhibiting VEGFR2 endocytosis, thereby prolonging pro-angiogenic signaling [137]. Collectively, these findings establish Gal-3 as a multifunctional regulator in AMD pathogenesis, influencing critical processes including cellular adhesion, inflammatory responses, and neovascularization (Fig. 7).

Fig. 7.

The specific mechanisms of action and signaling pathways of Gal-3 across age-related macular degeneration.

This study elucidates the pivotal role of Gal-3 in AD and age-related diseases, demonstrating that elevated Gal-3 expression induces functional impairments across multiple organ systems including neural tissue, vasculature, pancreatic islets, and articular cartilage. These findings establish a novel theoretical framework for understanding molecular mechanisms underlying organ homeostasis and disease pathogenesis. Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7 comprehensively illustrate mechanistic actions and associated signaling pathways of Gal-3 in age-related diseases. Our systematic analysis reveals that Gal-3 establishes establish context-dependent pathological networks across diverse age-related conditions through its regulation of inflammatory responses, suggesting inflammation as a principal common mechanism linking Gal-3 to aging-associated pathologies. As a crucial inflammatory modulator, Gal-3 exhibits consistently upregulated expression in these diseases and participates in multiple inflammation-related signaling cascades. The cross-disease synergistic effects of Gal-3 are particularly noteworthy. For instance, AD and T2DM share pathological mechanisms involving IR and chronic inflammation [138,139]. In T2DM patients, chronic hyperglycemia exacerbates AD pathology through oxidative stress and inflammatory pathways, while Gal-3 serves as a pleiotropic mediator participating in both T2DM-related insulin signaling impairment and AD-associated neuroinflammation via TLR4/NF-κB activation [140,141]. Similarly, in AS and T2DM, Gal-3 bridges metabolic dysregulation and vascular pathology by promoting foam cell formation and endothelial dysfunction [142]. Therefore, while emphasizing neurological disorders (AD, PD), we also examine Gal-3's role in systemic aging-related conditions (T2DM, AS, OA, AMD) that frequently co-occur with or influence neurodegeneration. This systems perspective aligns with contemporary approaches to studying multimorbidity in aging populations. These cross-pathology associations highlight Gal-3's potential as a therapeutic “multifaceted regulator” for multiple age-related diseases. However, this shared pathological role should not obscure the disease-specific contexts of Gal-3 action. While this review comprehensively examines Gal-3's role across multiple aging-related diseases, it is important to note that these conditions have distinct etiologies and pathophysiological mechanisms. The shared involvement of Gal-3 does not imply identical disease processes, but rather highlights its pleiotropic nature as a modulator of common pathological features such as chronic inflammation and oxidative stress. Therapeutic strategies must therefore be tailored to specific disease contexts and stages, considering Gal-3's dual roles in different tissues and pathological conditions. A key discovery of this study is the tissue-specific and dynamically regulated nature of Gal-3 expression. In AD patients, Gal-3 levels show strong positive correlations with Aβ burden and cognitive decline severity, whereas in T2DM patients, circulatory and pancreatic islet Gal-3 upregulation closely associates with IR and poor glycemic control. Importantly, Gal-3 demonstrates context-dependent pleiotropy: under certain pathological conditions, Gal-3 deficiency may paradoxically accelerate disease progression. For example, Gal-3 knockout mice develop more severe obesity and metabolic disorders under high-fat diet conditions [143]. This apparent paradox suggests Gal-3 may exert diametrically opposed biological functions depending on disease stage and microenvironment. In early AD, Gal-3 may provide neuroprotection by enhancing microglial phagocytic activity, while in chronic stages it may transition to pro-inflammatory roles. Similarly, in T2DM, systemic Gal-3 deficiency may exacerbate metabolic inflammation, whereas localized pancreatic overexpression may directly impair β-cell function [93,144]. Therefore, a key challenge in developing Gal-3-targeted therapies lies in its dualistic biological functions. This context-dependence necessitates spatiotemporal precision in therapeutic targeting. Potential strategies include: (1) Stage-specific intervention: Inhibiting Gal-3 primarily during chronic inflammatory phases while preserving its beneficial roles in early disease or homeostasis (2) Localized delivery: Using tissue-targeted formulations (e.g., nanoparticles, intra-articular injections for OA) to minimize systemic effects (3) Functional modulation: Developing allosteric modulators that selectively block specific protein interactions (e.g., Gal-3-TREM2) rather than global inhibition. Table 1, Table 2 comprehensively summarize Gal-3 expression patterns and associated regulatory networks in clinical populations and experimental models, providing crucial references for targeted Gal-3 interventions. Future investigations should prioritize elucidation of Gal-3's dynamic regulatory networks and tissue-specific mechanisms to facilitate development of personalized therapeutic strategies for age-related disorders.

Table 1.

Gal-3 alterations among patients with aging-related diseases.

Disease Categories	Participants	Age	Cells or tissues	Experimental Methods	Gal-3 Alterations	Results	Reference
AD	EG: AD patients (n ​= ​31) vs. CG (n ​= ​50)	EG: 66.8 ​± ​7.8 years; CG: 74.9 ​± ​7.3 years	Serum and CSF	ELISA	Increase	Elevated Gal-3 induces inflammatory response and apoptosis, and neurodegenerative damage	Ashraf et al., 2018
AD	EG: AD patients (n ​= ​5) vs. CG (n ​= ​6)	NA	Cortex	WB	Increase	Gal-3 directly interacts with TREM2 in microglia and stimulates the TREM2/DAP12 signaling pathway	Boza-Serrano et al., 2019
AD	EG: AD patients (n ​= ​4) vs. CG (n ​= ​4)	NA	Frontal lobe tissue	IHC; WB	Increase	The serum Gal-3 expression in patients with AD is elevated, and it increases with the severity of memory loss	Tao et al., 2020
AD	EG: AD patients (n ​= ​119) vs. CG (n ​= ​36)	EG: 62.7 years; CG: 72.4 years	CSF	ELISA; WB; IHC	Increase	Gal-3 drives microglial inflammatory response through TREM2, causing Aβ deposition	Boza-Serrano et al., 2022
AD	EG: AD patients (n ​= ​4) vs. CG (n ​= ​4)	NA	Cortex and hippocampus	Immunoblotting; IHC	Increase	Gal-3 mediates the spread of tau protein through extracellular vesicles	Siew et al., 2024
AD	EG: AD patients (n ​= ​57) vs. CG (n ​= ​61)	EG: 79.05 ​± ​6.96 years; CG: 77.65 ​± ​7.665 years	Serum	ELISA	Increase	In patients with AD, serum Gal-3 levels increase with the severity of the disease	Yazar et al., 2020
AD	EG: AD patients (n ​= ​41) vs. CG (n ​= ​46)	EG: 71.2 ​± ​8.1 years; CG: 69.8 ​± ​10.9 years	Serum	ELISA	Increase	The serum Gal-3 levels in patients with AD are elevated and exacerbate the degree of cognitive impairment	Wang et al., 2015
PD	EG: IPD patients (n ​= ​60) vs. CG (n ​= ​30)	EG: 72.5 (49–88) years; CG: 72 (61–87) years	Serum	ELISA	Increase	Gal-3 is involved in disease processes such as immune activation, regulation, and inflammation in Parkinson's disease	Cengiz et al., 2019
PD	EG: PD patients (n ​= ​60) vs. CG (n ​= ​30)	EG: 61.3 ​± ​6.0 years	Serum	ELISA	Increase	The higher the level of Gal-3, the more severe the patient's motor impairments	Xu et al., 2024
PD	EG: PD patients (n ​= ​6)	NA	Substantia nigra	ELISA	Increase	Gal-3 leads to neuronal damage by promoting the formation of toxic α-synuclein strains	García-Revilla et al., 2023
PD	EG: PD patients (n ​= ​56) vs. CG (n ​= ​46)	EG: 64.79 ​± ​10.15 years; CG: 65.91 ​± ​9.78 years	Serum	ELISA	Increase	Gal-3 activates the NF-κB pathway by binding to TLR4 or the NLRP3 inflammasome, leading to the secretion of IL-1β and TNF-α	Wu et al., 2021
PD	EG: IPD patients (n ​= ​48) vs. CG (n ​= ​63)	EG: 70.44 ​± ​5.66 years; CG: 70.30 ​± ​5.16 years	Serum	ELISA	Increase	The serum Gal-3 levels in IPD patients are significantly higher than those in healthy controls, and they further increase with disease progression	Yazar et al., 2019
DM	EG: DM patients (n ​= ​57) vs. CG (n ​= ​56)	EG: 49.2 ​± ​9.4 years; CG: 49.0 ​± ​9.3 years	Serum	ELISA	Increase	Gal-3 is an independent predictor of diabetes and mediates the development of diabetes through inflammation	Yilmaz et al., 2014
DM	EG: DM patients (n ​= ​135) vs. CG (n ​= ​270)	EG: 53.42 ​± ​11.37 years; CG: 53.42 ​± ​11.35 years	Serum	ELISA	Increase	Gal-3 interacts with inflammatory factors such as TNF-α and IL-6 to enhance inflammatory signaling, exacerbating insulin resistance and β-cell dysfunction	Lin et al., 2021
DM	EG: DM patients (n ​= ​88) vs. CG (n ​= ​41)	EG: Group 1: 54.76 ​± ​8.70 years; group 2: 52.65 ​± ​10.51; CG: 41.29 ​± ​10.22 years	Serum	ELISA	Increase	Gal-3 promotes the development of DM by participating in pathways such as inflammation, insulin resistance, and β-cell dysfunction	Atalar et al., 2019
AS	EG: AS patients (n ​= ​8) vs. CG (n ​= ​8)	NA	Serum; plaques; HUVECs	ELISA; WB	Increase	Gal-3 exerts pro-inflammatory effects by activating the integrin β1/RhoA/JNK signaling pathway	Chen et al., 2018
AS	EG: AS patients (n ​= ​158) vs. CG (n ​= ​199)	EG: 62–72 years; CG: 49–62 years	Serum	RT-PCR; ELISA	Increase	Gal-3 promotes the activation of monocytes/macrophages and inflammatory responses through NADPH oxidase-dependent ROS release	Madrigal-Matute et al., 2014
OA	EG: OA patients (n ​= ​9)	54–80 years	Knee cartilage	Glycohistoche-mical analysis	Increase	Gal-3 levels are elevated in OA cartilage, especially in severely degenerated areas	Toegel et al., 2013
OA	EG: OA patients (n ​= ​15) vs. CG (n ​= ​13)	EG: 65 years; CG: 63 years	Articular cartilage	IHC; RT-PCR	Increase	After MMP-13 cleaves Gal-3, it accelerates ECM degradation and chondrocyte apoptosis	Guevremont et al., 2004
OA	EG: OA patients (n ​= ​15) vs. CG: unknown	EG: 50–81 years; CG: unknown	Articular cartilage	IHC; RT-qPCR; ELISA	Increase	Gal-3 drives inflammation and matrix degradation through the NF-κB pathway, promoting the progression of OA	Weinmann et al., 2016
OA	EG: OA patients (n ​= ​272) vs. CG (n ​= ​93)	EG: 62–69 years; CG: 65–72 years	Plasma and synovial fluid	RT-qPCR; ELISA	Increase	Gal-3 activates the PI3K/Akt pathway, promoting the expression of inflammatory mediators (NO, IL-6) and catabolic genes (IL-6, NF-κB, MMP-13), while inhibiting the expression of anabolic genes (ACAN, SOX-9)	Udomsinprasert al., 2023
AMD	EG: AMD patients (n ​= ​16) vs. CG (n ​= ​14)	65 years old and above	Retinal pigment epithelium	SILAC	Increase	Gal-3 promotes cell adhesion and matrix deposition by binding to ECM components such as fibronectin, forming the core structure of drusen	An et al., 2006
AMD	EG: AMD patients (n ​= ​24) vs. CG (n ​= ​25)	EG: 70–87 years; CG: 70–87 years	Macular Bruch membrane/choroid complex	LC MS/MS iTRAQ; WB	Increase	Gal-3 binds to AGEs, triggering an inflammatory response that leads to structural and functional changes in the Bruch's membrane/choroid complex in the macular region	Yuan et al., 2010
AMD	EG: AMD patients (n ​= ​3) vs. CG (n ​= ​15)	Over 70 years old	Retina	ScRNA-seq; IHC	Increase	Gal-3 plays a protective role in the pathogenesis of AMD through microglia-mediated phagocytosis and TREM2-dependent signaling pathways	Yu et al., 2024
AMD	EG: AMD patients (n ​= ​70) vs. CG (n ​= ​59)	EG: 70 years; CG: 50 years	Retina	IHC	Increase	Gal-3 participates in the pathogenesis of AMD by promoting microglial activation and pro-inflammatory pathways, ultimately leading to retinal damage and vision loss	Tabel et al., 2022
AMD	EG: AMD patients (n ​= ​56) vs. CG (n ​= ​30)	EG: 65.25 ​± ​2.96 years; CG: 65.43 ​± ​2.75 years	Serum	ELISA	Increase	Gal-3 promotes the pathogenesis of AMD by increasing inflammatory responses and oxidative stress	Sumer et al., 2024

Abbreviation: Aβ, amyloid beta; ACAN, aggrecan; AD, Alzheimer's disease; AMD, aging-related macular degeneration; AS, atherosclerosis; CG, control Group; CSF, cerebrospinal fluid; DAP12, DNAX-activation protein 12; DM, diabetes mellitus; ECM, extracellular matrix; EG, experimental Group; ELISA, Enzyme-linked immunosorbent assay; HUVECs, human umbilical vascular endothelial cells; IHC, immunohistochemistry; IPD, idiopathic Parkinson's disease; Gal-3, galectin-3; JNK, c-Jun N-terminal kinase; LC MS/MS iTRAQ, isobaric tags for relative and absolute quantitation; MMP-13, collagenase-3; NA, not available; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; OA, osteoarthritis; PD, Parkinson's disease; ROS, reactive oxygen species; RT-PCR, real-time quantitative polymerase chain reaction; RT-qPCR, real-time quantitative polymerase chain reaction; ScRNA-seq, single-cell RNA-sequencing; SILAC, stable isotope labeling by amino acids in cell culture; SOX-9, SRY-Box 9; TLR4, toll-like receptor 4; TREM2, triggering receptor expressed on myeloid cells 2; WB, western blot.

Table 2.

Gal-3 alterations among animal models with aging-related diseases.

Disease Categories	Participants	Age	Cells or tissues	Experimental Methods	Gal-3 Alterations	Results	Reference
AD	APP/PS1mice	NA	Cortex; hippocampus	IHC; WB	Increase	Gal-3 promotes Aβ oligomerization by activating microglia and reducing neprilysin expression	Tao et al., 2020
AD	5 ​× ​FAD mice	6 months and 18 months	Cortex; hippocampus	IHC; WB; ELISA	Increase	Gal-3 directly interacts with TREM2 in microglia and stimulates the TREM2/DAP12 signaling pathway	Boza-Serrano et al., 2019
AD	C57BL/6 mice (male)	23 months	Hippocampus	WB; ELISA; RT-qPCR	Increase	Gal-3 promotes inflammatory responses through the TLR4/NF-κB signaling pathway, leading to cognitive decline in mice	Chen et al., 2022
PD	C57BL/6 mice	12–14 weeks	Ventral mesencephalon	IHC; WB	Increase	Gal-3 exacerbates dopaminergic neuronal damage by modulating the aggregation morphology of α-synuclein and driving neuroinflammation	García-Revilla et al., 2023
PD	C57BL/6 mice	8–12 weeks	Striatum; substantia nigra	RT-qPCR	Increase	Gal-3 participates in the pathology of PD through microglial activation and the occurrence of inflammatory responses	Belloli et al., 2017
PD	C57BL/6 mice	3 months	Olfactory bulb	WB	Increase	Gal-3 induces an increase in iNOS expression and the release of pro-inflammatory cytokines (such as IL-1β, IL-12)	Boza-Serrano et al., 2014
DM	C57BL/6J mice	8–10 weeks	Pancreatic β cell; serum	IHC	Increase	Gal-3 leads to insulin resistance and glucose metabolism disorders by enhancing β-cell apoptosis and oxidative stress, promoting M1 macrophage infiltration in islets, and activating the TLR4 inflammatory pathway	Petrovic et al., 2020
DM	C57BL/6 mice	8–12 weeks	Serum	WB; qPCR; ELISA	Increase	Gal-3 binds to the insulin receptor, inhibiting its tyrosine phosphorylation and downstream signaling (IRS1/PI3K/Akt), leading to insulin resistance	Li et al., 2017
DM	C57BL6/J mice	8–12 weeks	Pancreatic β cell; serum	QPCR	Increase	Gal-3 impairs insulin secretion by inhibiting the β-cell calcium signaling pathway (CACNG1/L-VGCCs axis), leading to diabetic β-cell dysfunction	Jiang et al., 2014
AS	ApoE−/− mice (male); C57BL/6 mice (male)	26 and 36 weeks	Atherosclerotic plaque	IHC; WB; ELISA	Increase	Gal-3 participates in the inflammatory progression of atherosclerotic plaques through macrophage-dependent inflammatory amplification	Lee et al., 2013
AS	ApoE−/−/C57BL/6 (male)	8 weeks	Coronary artery	WB; ELISA; RT-qPCR	Increase	Gal-3 promotes inflammation and plaque instability by targeting and regulating Inc-ARSR, thereby activating the PI3K/Akt pathway	Xu et al., 2021
OA	WT mice	6 weeks and 4months	Articular cartilage	WB	Increase	Gal-3 participates in the pathogenesis of osteoarthritis through the NF-κB pathway	Boileau et al., 2007
AMD	C57BL/6 mice	8–20 weeks	Retina	ScRNA-seq; IHC	Increase	Gal-3 regulates the migration and phagocytic function of microglia through the TREM2 signaling axis, playing a protective role in retinal degeneration	Yu et al., 2024
AMD	C57BL/6 mice	6–8 weeks	RPE/Choroidal complex	WB; ELISA; RT-qPCR	Increase	Gal-3 is upregulated through the hypoxia/HIF-1α axis, promoting neovascularization and fibrosis	Wu et al., 2024

Abbreviation: Aβ, amyloid beta; AD, Alzheimer's disease; Akt, protein kinase B; ApoE^−/−, apolipoprotein E knockout; AMD, aging-related macular degeneration; AS, atherosclerosis; CACNG1, calcium voltage-gated channel auxiliary subunit gamma 1; DAP12, DNAX-activation protein 12; DM, diabetes mellitus; ELISA, Enzyme-linked immunosorbent assay; HIF-1α, hypoxia-inducible factor 1 alpha; IHC, immunohistochemistry; iNOS, inducible nitric oxide synthase; IRS1, insulin receptor substrate 1; L-VGCCs, L-type voltage-gated calcium channels; OA, osteoarthritis; PD, Parkinson's disease; PI3K, phosphoinositide 3-Kinase; QPCR, quantitative polymerase chain reaction; RT-PCR, real-time quantitative polymerase chain reaction; RT-qPCR, real-time quantitative polymerase chain reaction; scRNA-seq, single-cell RNA-sequencing; TLR4, toll-like receptor 4; TREM2, triggering receptor expressed on myeloid cells 2; WB, western blot.

Treatment prospects

Given the pivotal role of Gal-3 in the pathogenesis and progression of age-related disorders, therapeutic strategies targeting the Gal-3 signaling network emerge as a promising approach for mitigating or reversing aging-associated pathologies. This section comprehensively examines the therapeutic potential of Gal-3 in age-related disorders, systematically evaluating various Gal-3-targeted interventions, their therapeutic efficacy, and clinical significance, as summarized in Table 3. The pro-inflammatory characteristics of Gal-3 position it as a crucial modulator of the aging microenvironment. Importantly, the pathological mechanisms underlying age-related diseases exhibit multidimensional regulatory features, where Gal-3-mediated chronic inflammation cooperates with oxidative stress, autophagy dysfunction, and apoptotic pathway dysregulation to form an intricate pathological network. This complexity suggests that disease progression results from the synergistic effects of multiple pathological factors, thereby highlighting the limitations of single-target therapeutic approaches. Gal-3-targeted therapies demonstrate considerable potential in combating age-related disorders, warranting further investigation to elucidate their precise mechanisms and clinical applicability. Fig. 8 provides a comprehensive overview of current therapeutic prospects for age-related diseases, detailing the molecular pathways associated with relevant therapeutic targets.

Table 3.

Therapeutic strategies targeting Gal-3 in aging-related diseases in different models.

Intervention Strategies	Therapeutics	Disease Categories	Design and subjects	Interventions (dose, time, method of administration)	Gal-3 Alterations	Results	Reference
Targeting molecules	FTS	AD	C57BL/6J mice (male, 2 months)	3 ​mg/kg, 14days, i.p.	Decrease	FTS reduces the production of Aβ and accelerates its degradation by inhibiting the Gal-3/JNK/PS1 signaling pathway	Qiu et al., 2024
	MG-257	AD	BV2 cells; BWZ cells	2.5, 5, 10 ​μM	Decrease	MG-257 exerts anti-inflammatory effects by inhibiting the interaction between Gal-3 and TREM2	Gabr et al., 2020
	TD139	AMD	Lgals-3 KO mice (8-10w)	15 ​mg/kg/d, 5 days, i.p.	Decrease	TD139 reduces the expression of retinal inflammatory genes by inhibiting Gal-3 expression	Tabel et al., 2022
Natural compounds	MCP	AD	Wistar rats (male, 6w)	100 ​mg/kg/d, 7 days, p.o.	Decrease	MCP alleviates neuroinflammation, antioxidant activity by inhibiting Gal-3 expression	Akgöl et al., 2024
	MCP	DM	Wistar rats (male)	100 ​mg/kg/d, 4 weeks, p.o.	Decrease	MCP exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting Gal-3, thereby reducing the levels of MDA, TNF-α, iNOS, TGF-βRII, and caspase-3	Mahmoud et al., 2024
	MCP	AS	ApoE−/− mice (male, 8w)	1 ​% MCP, 4 weeks, p.o.	Decrease	MCP delays the progression of AS by inhibiting Gal-3, thereby promoting the adhesion and migration of monocytes	Lu et al., 2017
	MCP-HA	OA	Rabbits (equal numbers of male and female)	0.5 ​mL 1 ​% HA gel ​+ ​500 ​μg/mL MCP, once/week for 5 weeks, i.a.	Decrease	MCP-HA alleviates OA by inhibiting Gal-3-mediated inflammatory responses, downregulating the IL-17 and NF-κB signaling pathways, and reducing cartilage degradation and synovial inflammation	Chen et al., 2024
	LM-pectin	DM	Cells and islets	0.5, 1, 2 ​g/L (DM5, DM18, DM69), 24 ​h, incubate	Decrease	Pectin reduces the level of β-cell apoptosis by targeting Gal-3 to block its pro-apoptotic and pro-inflammatory signaling pathways	Hu et al., 2020
	D30	AD	ICR mice (male and female, 8w); thy1-eGFP mice (male, 8w)	10, 20, 40 ​mg/kg, 21 days, i.p.	Decrease	D30 inhibits the expression of Gal-3 through the PI3K/Akt/mTOR signaling pathway, thereby alleviating fAβ	Liu et al., 2025
	D30	AD	5 ​× ​FAD mice (male, 5 months); Thy1-eGFP mice (male, 5 months)	20 ​mg/kg/d, 1 and 3months, p.o.	Decrease	D30 blocks the Gal-3/TREM2 signaling axis to improve neuroinflammation and synaptic injury in AD	Liu et al., 2025
	XN; 8-PN	DM	C57B1/6 mice (male, 6w)	XN and 8-PN were dissolved in ethanol (0.1 ​% final concentration)	Decrease	XN and 8-PN exert antioxidant effects by downregulating Gal-3 expression	Luís et al., 2018
	Quercetin	AS	ApoE−/− mice (male, 6w)	100 ​mg/kg, 16 weeks, p.o.	Decrease	Quercetin reduces AS inflammation in macrophages by inhibiting the Gal-3/NLRP3 signaling pathway	Li et al., 2021
	Piperine	DM	C57B1/6 mice (male, 7w)	15, 30 ​mg/kg/d, i.g.	Decrease	Piperine targets Gal-3 to regulate the mTOR/S6/4E-BP1 pathway, thereby inhibiting M1 polarization of macrophages, alleviating islet inflammation, and reversing β-cell de-differentiation	Yuan et al., 2021
Other drugs	Melatonin	AS	ApoE−/− mice (male, 8w)	20 ​mg/kg/d, 12 weeks, p.o.	Decrease	Melatonin reduces the expression of Gal-3, inhibits the NF-κB pathway, and enhances autophagy, melatonin inhibits the binding of Gal-3 to CD98, increasing autophagy and anti-inflammatory effects through the PI3K/AKT pathway	Wang et al., 2023
	Statin	AS	ApoE−/− mice (male, 36w)	0.57 ​mg/kg/d, 5days, i.g.	Decrease	Statin reduces the expression of Gal-3 by decreasing macrophage infiltration and activity	Lee et al., 2013
	Statin	AS	Human (average 70 years)	More than 1 months, p.o.	Increase	Long-term statin therapy increases the expression of Gal-3 in human carotid artery plaques, suggesting that Gal-3 promotes plaque stability by inhibiting inflammatory responses	Kadoglou et al., 2015
	Statin	AS	ApoE−/− mice (male, 8-10w)	40 ​mg/kg/d, 9 weeks, p.o.	Increase	Statin's treatment reduces the accumulation of Gal-3-negative macrophages in AS plaques, maintaining the anti-inflammatory effects of Gal-3	Di Gregoli et al., 2020
	DLT	DM	Db/db mice (male, 5w); C57BL/6J mice (male, 5w)	1 ​g/kg, 16 weeks, i.g.	Decrease	DLT ameliorates IR by downregulating Gal-3 expression, thereby modulating the IRS-1/PI3K/Akt insulin signaling pathway and the SREBP-1/FAS signaling pathway	Pang et al., 2022

Abbreviation: 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; 8-PN, 8-prenylnaringenin; Aβ, amyloid beta; AD, Alzheimer's disease; ApoE^−/−, apolipoprotein E knockout; AMD, aging-related macular degeneration; ARTY-DUO, hyaluronic acid associated to chitlac; AS, atherosclerosis; D30, (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one; DLT, Danlou Tablets; DM, diabetes mellitus; FAS, fatty acid synthase; FTS, farnesylthiosalicylic acid; ICR, Institute of Cancer Research; iNOS, inducible nitric oxide synthase; IR, insulin resistance; IRS-1, insulin receptor substrate 1; JNK, c-Jun N-terminal kinase; LM-pectin, low methyl-esterified pectin; OA, osteoarthritis; PD, Parkinson's disease; MDA, malondialdehyde; MCP, modified citrus pectin; MCP-HA, modified citrus pectin-hyaluronic acid; NLRP3, NLR family pyrin domain containing 3; PI3K, phosphoinositide 3-kinase; PS1, presenilin 1; S6, ribosomal protein S6; SREBP-1, sterol regulatory element-binding protein 1; TGF-βRII, transforming growth factor-beta receptor type II; TREM2, triggering receptor expressed on myeloid cells 2; XN, xanthohumol.

Fig. 8.

Therapeutic prospects of aging-related diseases targeting Gal-3.

Targeting molecules

Farnesylthiosalicylic acid (FTS, salirasib) represents a novel small-molecule inhibitor targeting Ras protein signal transduction [145]. Its primary mechanism involves competitive displacement of mutant F-Ras protein from membrane binding sites through interaction with galectin proteins, effectively inhibiting Ras membrane localization and subsequent downstream signaling activation [146]. This specific inhibition potently suppresses tumor cell proliferation and metastasis, demonstrating broad-spectrum antitumor activity [147,148]. Recent investigations reveal FTS exhibits multi-target therapeutic effects through modulation of diverse signaling pathways. In AD-related neuroinflammation studies, Qiu et al. demonstrated FTS exerts multi-faceted neuroprotection via Gal-3 targeting: (1) significantly reducing total Gal-3 expression and membrane localization in Aβ1-42 mouse models while promoting cytoplasmic accumulation and lysosomal degradation; (2) inhibiting Gal-3/TLR4 binding and subsequent NF-κB pathway activation, thereby decreasing pro-inflammatory cytokine release (IL-1β, IL-6, TNF-α, NO); (3) reducing Aβ production and enhancing its clearance through Gal-3/JNK/PS1 pathway inhibition, ultimately improving synaptic plasticity and cognitive function [57].

MG-257, a novel quinoline-pyrazole compound, demonstrates high-affinity binding to Gal-3's CRD, competitively inhibiting Gal-3/TREM2 interaction and subsequent TREM2/DAP12 pathway activation. Its neuroprotective effects manifest through dual mechanisms: direct inhibition of Gal-3-mediated DAP12 signaling and significant reduction of pro-inflammatory factors (TNF-α, IL-12, IL-8). This compound exhibits exceptional multi-target regulation, high selectivity, and favorable pharmacokinetics, showing promising clinical potential for neurodegenerative disorders including AD [149].

TD-139, a thiogalactoside analog, functions as a potent and selective Gal-3 inhibitor through competitive CRD binding [150], demonstrating therapeutic efficacy in inflammatory and fibrotic diseases [151]. In AMD models, TD-139 treatment significantly attenuates microglial migration and morphological changes (e.g., branched-to-amoeboid transition), while reducing expression of pro-inflammatory mediators (iNOS, IL-6, CCL2). Mechanistically, TD-139 suppresses retinal inflammation by inhibiting the Gal-3/JAK/STAT pathway and downregulating key inflammatory genes (TNF-α, IL-1β) [135].

Natural compounds

Modified citrus pectin (MCP), a semi-synthetic β-galactose-rich polysaccharide derived from citrus plants, competitively binds to the CRD of Gal-3, thereby modulating critical pathophysiological processes including cell adhesion, inflammation, and signal transduction [[152], [153], [154]]. As a chemically modified low-molecular-weight pectin, MCP demonstrates superior bioavailability through intestinal absorption, exhibiting diverse biological activities encompassing antioxidant, anti-inflammatory, antifibrotic, and antitumor effects [[154], [155], [156]]. In neuroinflammatory and neurodegenerative contexts, MCP attenuates Gal-3-mediated microglial activation and subsequent pro-inflammatory cytokine release [47]. Specifically in AD models, MCP significantly reduces pro-inflammatory factors (TNF-α, IL-6) while upregulating brain-derived neurotrophic factor (BDNF) expression through TLR4/MyD88/NF-κB pathway inhibition, concurrently enhancing SOD activity and mitigating lipid peroxidation [69]. In AS, MCP disrupts Gal-3-integrin β1/VCAM-1 interactions, inhibiting monocyte-endothelial adhesion and subsequent plaque formation [157]. In T2DM and its complications, Gal-3 acts as a scavenger receptor for AGEs, and its inhibition reduces AGE-mediated vascular damage. MCP inhibits Gal-3, thereby decreasing MDA levels while elevating catalase (CAT) and glutathione (GSH) antioxidant markers [95]. In OA, MCP-hyaluronic acid (HA) complexes demonstrate synergistic therapeutic effects by downregulating IL-17/NF-κB signaling and inhibiting MMP activity [158]. Low-methoxyl pectin (LM-pectin), another bioactive pectin variant, exhibits similar Gal-3-inhibitory properties, particularly in protecting pancreatic β-cells through mitochondrial apoptosis pathway modulation [96].

The novel anti-AD compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30) demonstrates dual targeting of Gal-3 and Aβ pathology. With superior specificity, D30 competitively inhibits Gal-3-TREM2 interactions, attenuating microglial activation and pro-inflammatory cytokine release (IL-6, TNF-α) [159]. In 5 ​× ​FAD transgenic mice, D30 reduces Aβ production and aggregation by downregulating APP and PS1 expression while activating neuroprotective PI3K/AKT/mTOR signaling [58,160].

Xanthohumol (XN), an isoprenylated flavonoid from hops, and its metabolite 8-prenylnaringenin (8-PN) exhibit potent antioxidant and anti-inflammatory properties through distinctive chalcone and isopentenyl structural motifs [[161], [162], [163]]. In high-fat diet-induced T2DM models, both compounds normalize aberrant Gal-3 expression in hepatic and renal tissues, with 8-PN demonstrating particular efficacy in ameliorating hyperglycemia-induced endothelial dysfunction [164]. The phytoestrogenic 8-PN additionally modulates oxidative stress and inflammatory responses critical to diabetes pathogenesis [163,165].

Quercetin, another naturally occurring flavonoid compound abundantly present in Fagaceae plants such as Quercus and Castanopsis, exhibits diverse pharmacological properties, including antitumor, antioxidant, anti-inflammatory, and antibacterial activities, with its anti-inflammatory effects being particularly prominent [166]. Recent studies have demonstrated that quercetin mitigates macrophage-mediated inflammatory responses and reduces lipid accumulation through inhibition of the Gal-3/NLRP3 signaling pathway, thereby attenuating atherosclerotic lesions and conferring anti-AS effects [167]. These findings elucidate a novel molecular mechanism underlying the therapeutic potential of flavonoids in managing diabetic complications and AS. However, the precise role of Gal-3 in aging-related pathologies remains to be fully elucidated, necessitating further investigation to assess its viability as a therapeutic target. Future research should prioritize comprehensive metabolic studies and randomized clinical trials to evaluate the long-term efficacy and safety profiles of these polyphenolic compounds.

Piperine is an amide alkaloid extracted from the dried mature fruits or seeds of Piper nigrum L., a plant belonging to the Piperaceae family [168]. Piperine exerts a range of metabolic benefits through multiple mechanisms in both in vivo and in vitro settings, demonstrating unique therapeutic potential [169]. Specifically, piperine significantly ameliorates metabolic syndrome by alleviating IR, exerting anti-obesity effects, modulating lipid metabolism, inhibiting hepatic steatosis, and regulating gut microbiota [170,171]. Studies have shown that in obesity, M1 polarization of macrophages (pro-inflammatory phenotype) in adipose tissue and pancreatic islets, along with the excessive secretion of inflammatory factors (e.g., Gal-3, IL-1β), directly impairs pancreatic β-cell function, leading to insulin secretion dysfunction [172]. Yuan et al. investigated the effects of piperine intervention in a high-fat diet-induced obese mouse model. The results demonstrated that piperine targets Gal-3 to regulate the mTOR/S6/4E-BP1 pathway, thereby suppressing macrophage infiltration and M1 polarization, mitigating islet inflammation, and reversing β-cell dedifferentiation. Furthermore, Gal-3 overexpression induces β-cell dedifferentiation, characterized by downregulation of Pdx1 (a marker of β-cell maturity) and upregulation of ALDH1A3 (a dedifferentiation marker). Piperine partially restored Pdx1 expression and reduced ALDH1A3 levels by inhibiting Gal-3-mediated inflammatory signaling [94].

Other drugs

Melatonin (Mel), an indoleamine neuroendocrine hormone predominantly synthesized and secreted by the pineal gland, plays a pivotal role in modulating immune responses, circadian rhythms, and oxidative stress defense mechanisms [173]. Emerging evidence highlights Mel's therapeutic potential in age-related pathologies, with particular efficacy in neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes [174,175]. Notably, melatonin demonstrates distinctive advantages in AS management through its regulatory effects on Gal-3 expression and functionality. Current research establishes that Gal-3 exacerbates AS pathogenesis by facilitating inflammatory cytokine release via NLRP3 inflammasome interaction and NF-κB signaling pathway activation [167]. Furthermore, Gal-3 contributes to foam cell formation and vascular endothelial dysfunction, thereby accelerating AS progression [176]. Mechanistically, Mel downregulates Gal-3 expression and suppresses NF-κB nuclear transcription factor activity, which subsequently promotes TFEB nuclear translocation and enhances autophagic flux. Concurrently, Mel counteracts Gal-3/CD98 complex-mediated autophagy inhibition via the PI3K/AKT pathway [109]. These mechanistic insights establish a robust theoretical foundation for Mel's therapeutic application in AS treatment.

Statins are first-line pharmacological agents for the management of cardiovascular diseases and dyslipidemia [177]. Emerging evidence suggests that their anti-atherosclerotic effects may be mediated, in part, through modulation of Gal-3 expression and function, although the precise mechanisms and the role of Gal-3 remain subjects of ongoing debate [116,178,179]. Lee et al. demonstrated that atorvastatin significantly downregulated Gal-3 expression in atherosclerotic plaques of apoE^−/− mice, with this reduction correlating with decreased macrophage infiltration, thereby positioning Gal-3 as a potential inflammatory biomarker reflecting plaque burden [116]. In contrast, Di Gregoli et al. reported that statin therapy reduces the accumulation of Gal-3-negative macrophages in atherosclerotic lesions while preserving the anti-inflammatory and profibrotic properties of Gal-3 through inhibition of MMP12-mediated Gal-3 proteolysis, consequently attenuating plaque progression [179]. Similarly, Kadoglou et al. observed that prolonged statin treatment upregulated Gal-3 expression in human carotid plaques concomitant with reduced macrophage infiltration, suggesting a potential plaque-stabilizing role of Gal-3 via suppression of inflammatory responses [178]. This apparent dichotomy in Gal-3 function may be context-dependent, influenced by its cellular localization and disease progression stage: intracellular Gal-3 in macrophages appears to exert protective effects by mitigating pro-inflammatory polarization and potentiating TGF-β signaling, whereas during advanced plaque development, MMP12-mediated cleavage of Gal-3 may lead to functional loss and exacerbation of inflammation. Statins may orchestrate plaque stabilization through tissue-specific regulation of Gal-3 expression or activity via distinct molecular pathways.

Danlou Tablet (DLT) is a composite traditional Chinese medicine formulation developed based on the theoretical framework of traditional Chinese medicine, representing a modernized refinement of classical prescriptions [180]. Comprising ten principal medicinal components-Trichosanthis Pericarpium, Allii Macrostemi Bulbus, Puerariae Lobatae Radix, Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Paeoniae Rubra Radix, Alismatis Rhizoma, Astragali Radix, Curcumae Radix, and Drynariae Rhizoma-DLT exhibits multifaceted pharmacological properties including anti-myocardial ischemia, anti-apoptotic, antioxidant, and lipid-modulating activities [181]. Emerging research has elucidated DLT's significant therapeutic potential in ameliorating IR and suppressing inflammatory cascades, mechanisms predominantly mediated through its modulation of Gal-3 expression. The seminal work by Pang et al. demonstrates that DLT ameliorates IR through dual-pathway regulation: (1) downregulation of Gal-3 expression with subsequent modulation of the IRS-1/PI3K/Akt insulin signaling axis, and (2) inhibition of the SREBP-1/FAS lipogenic pathway. Furthermore, DLT significantly suppresses the expression of key lipogenic regulators including sterol regulatory element-binding protein-1c and fatty acid synthase, thereby attenuating hepatic lipid accumulation and indirectly mitigating Gal-3 activation. This unique dual-targeted modulation of both glucose and lipid metabolism enables DLT to exert synergistic therapeutic effects on IR, effectively ameliorating hyperglycemia, dyslipidemia, and associated inflammatory pathologies. These findings not only provide mechanistic insights into DLT's therapeutic actions but also establish a robust theoretical foundation for subsequent clinical translation studies [182].

Conclusions and perspectives

Gal-3-targeted therapies have demonstrated broad therapeutic potential in aging-related diseases such as AD, yet their clinical translation remains constrained by several key challenges. First, the dualistic role of Gal-3 necessitates spatiotemporally precise intervention strategies—for instance, preserving its Aβ-clearing function in early-stage AD while suppressing its pro-inflammatory effects in chronic disease phases. Second, Gal-3 engages extensively in multiple signaling cascades, including TLR4/NF-κB, PI3K/AKT/mTOR, and JAK/STAT, forming a complex regulatory network linking inflammation, oxidative stress, and apoptosis in aging-related diseases. Consequently, monotherapeutic targeting of Gal-3 may prove insufficient to modulate these interconnected pathological mechanisms, potentially limiting therapeutic efficacy. Third, given Gal-3's ubiquitous expression across tissues and cell types, systemic inhibition risks disrupting its physiological roles in immune surveillance and tissue repair, as evidenced by exacerbated metabolic dysfunction in Gal-3 knockout mice under high-fat diet conditions—highlighting its context-dependent functional duality [183]. Fourth, although existing Gal-3 inhibitors (e.g., TD-139, MCP) exhibit promising anti-inflammatory and antioxidant effects in preclinical models, most studies remain confined to cellular or animal experiments, with critical gaps in pharmacokinetics, tissue-specific delivery, and long-term safety requiring further preclinical and clinical validation. Finally, the absence of reliable biomarkers to dynamically assess therapeutic response, coupled with interindividual variability in Gal-3 expression and functional states, complicates the development of personalized treatment regimens.

Current evidence indicates that Gal-3 orchestrates a shared molecular network across AD, PD, T2DM, AS, OA, and AMD by modulating core pathological mechanisms such as chronic inflammation, oxidative stress, and apoptotic signaling. To advance this field, future research should prioritize the following directions: (1) Future therapeutic development should focus on strategies that can selectively modulate Gal-3's detrimental effects while preserving or enhancing its beneficial roles, possibly through tissue-targeted delivery systems, allosteric modulators, or combination approaches with complementary mechanisms. (2) Developing combinatorial approaches to address disease complexity, as Gal-3 represents only one node in a broader pathological network. Synergistic interventions with other targets (e.g., anti-Aβ antibodies, insulin sensitizers) may enhance efficacy. During therapeutic development, potential drug-drug interactions and antagonistic effects must be rigorously evaluated. Systematic preclinical assessment of such combinatorial regimens should be conducted prior to clinical translation, with particular attention to pharmacokinetic interactions and tissue-specific responses. (3) Mitigating off-target effects of systemic Gal-3 inhibition through advanced delivery systems (e.g., tissue-targeted nanoparticles, surface-modified liposomes) or functional selectivity modulation to preserve physiological Gal-3 functions. (4) Accelerating clinical translation by validating Gal-3 inhibitors in human trials, particularly for multi-disease applications. (5) Establishing robust biomarker panels integrating imaging, fluid biomarkers, and genomic data to monitor therapeutic response and optimize personalized treatment.

In conclusion, Gal-3-targeted therapies offer a promising paradigm for mitigating aging-related diseases, yet overcoming translational hurdles—through mechanistic refinement, combinatorial strategies, and clinical validation—will be critical to realizing their full therapeutic potential.

Author contributions

Jiayu Yuan: Writing - original draft and Writing - review & editing; Xiaoyu Dong: Revising - original draft and Writing – review; Jianfei Nao: Writing - review & editing; Yan Gao: Supervision, Funding acquisition, and Conceptualization.

Funding

This work was supported by funding from the Natural Science Foundation of Liaoning Province (No. 2024-MS-024). The Joint Program of Science and Technology Program of Liaoning Province (No. 2023JH2/101800017).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.