Wnt/β-Catenin Signaling in Diabetic Complications: Mechanisms and Therapeutic Potential

Abstract

Diabetic complications, driven by chronic hyperglycemia and complex pathogenic mechanisms, are a major global health challenge, yet the basis of tissue-specific injury and repair remains unclear. Wnt/β-catenin signaling has emerged as an important regulator in these complications, but its role is highly context dependent, promoting pathological remodeling in some tissues while impairing repair in others. This review is distinguished by its integration of current evidence on the dual and often opposing roles of Wnt/β-catenin signaling across six major diabetic complications: diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cutaneous ulcers (DCU), diabetic cardiomyopathy (DCM), diabetic neuropathy, and diabetic osteoporosis (DOP). We first outline the major pathological features and clinical significance of each complication, highlighting the recurring observation that hyperglycemia often causes aberrant activation of this pathway in DN, DR, and DCM, where it promotes epithelial-to-mesenchymal transition, extracellular matrix accumulation, fibrosis, inflammation, and pathological angiogenesis. In contrast, we then examine conditions in which Wnt/β-catenin signaling is suppressed, particularly in DCU, DOP, and certain forms or stages of DPN, leading to impaired wound healing, reduced bone formation, and defective nerve regeneration. We subsequently analyze the cell type- and stage-specific mechanisms underlying these divergent effects, including cross-talk with oxidative stress, the renin–angiotensin system, and transforming growth factor-β signaling. Following a detailed discussion of emerging therapeutic strategies, such as LRP6-targeting biologics, small-molecule modulators, and agents derived from traditional Chinese medicine, we summarize preclinical evidence showing that carefully tuned, context-specific modulation of Wnt/β-catenin can improve both pathological and functional outcomes. This review is intended to clarify the potential mechanisms linking Wnt/β-catenin signaling to diabetic complications and to guide the rational development of new therapies that take into account its tissue-specific and stage-specific effects.

Introduction

Diabetes mellitus (DM) is a prevalent chronic disease of major global importance, caused by endocrine and metabolic disturbances.¹ It includes a heterogeneous group of disorders caused by impaired insulin secretion, reduced insulin sensitivity, or both, and can be classified into type 1 diabetes, type 2 diabetes, gestational diabetes, and other specific types. Persistent hyperglycemia is the main clinical feature of DM and is often accompanied by abnormalities in lipid and protein metabolism, which may eventually lead to chronic damage in multiple organs and tissues.¹ Recent estimates indicate that 529 million people were living with diabetes worldwide in 2021, with an age-standardized prevalence of 6.1%.² The economic burden is substantial: global health expenditure attributable to diabetes exceeded USD 966 billion in 2021, representing a 316% increase over the past 15 years.³ The number of people affected is projected to rise to more than 1.31 billion by 2050.² The World Health Statistics report (2023) lists diabetes among the top ten leading causes of disability-adjusted life-years (DALYs) globally.⁴ Moreover, the International Diabetes Federation (IDF) estimated 6.7 million diabetes-related deaths in 2021, corresponding to one death every five seconds.³

The long-term complications of diabetes are the major causes of diabetes-related disability and mortality. Patients with diabetes are at increased risk of developing both microvascular and macrovascular complications. The classical microvascular complications include diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), and diabetic cutaneous ulcers (DCU).^5,6 These complications are driven by chronic hyperglycemia and are closely associated with oxidative stress, inflammation, endothelial injury, and microvascular dysfunction, which together contribute to progressive damage in the kidney, retina, peripheral nerves, and skin tissues.^5–7 DN is one of the leading causes of chronic kidney disease and end-stage renal disease in patients with diabetes.⁷ DR is a major microvascular complication that progressively impairs vision and remains one of the leading causes of blindness in working-age adults.⁷ DPN is characterized by peripheral nerve dysfunction and commonly presents with pain, numbness, or sensory loss, thereby substantially reducing quality of life.⁷ Diabetic cutaneous ulcers (DCU) are also a common and difficult-to-treat complication of diabetes, closely associated with impaired wound healing, recurrent infection, neuropathy, microvascular dysfunction, and an increased risk of lower-extremity amputation.⁸ Macrovascular complications primarily include cardiovascular, cerebrovascular, and peripheral arterial disease, which may lead to myocardial infarction, stroke, and limb ischemia.^7,9 In addition, diabetes can contribute to myocardial injury and bone loss, leading to diabetic cardiomyopathy (DCM)¹⁰ and diabetic osteoporosis (DOP).¹¹ Despite major advances in disease management, effective curative therapies for diabetes and its complications remain limited. Their pathogenesis is complex and involves dysregulation of multiple intracellular signaling pathways. Among these, Wnt signaling has attracted increasing attention because of its reported involvement in a wide range of diabetic complications, including DN,¹² DPN,¹³ DR,¹⁴ DCU,⁸ DCM,¹⁰ and DOP.¹¹

Wnt signaling comprises a group of evolutionarily conserved pathways that play fundamental roles in embryonic development, organogenesis, and cell fate determination. It is also involved in the regulation of cell proliferation, differentiation, polarity, migration, and stem cell maintenance.^15–17 In recent years, increasing attention has been paid to the role of Wnt signaling in diabetes and its complications. However, although abnormal Wnt activity has been reported in a variety of diabetic complications, its exact role remains incompletely understood. In some settings, Wnt signaling appears to aggravate inflammation, fibrosis, oxidative stress, or vascular injury, whereas in others it may contribute to tissue repair, angiogenesis, or cellular survival.^15–17 These findings suggest that the effects of Wnt signaling are highly context-dependent and may vary according to tissue type, disease stage, and pathway branch involved. Therefore, clarifying the precise role of Wnt signaling in diabetic complications remains an important issue.

Wnt signaling is generally classified into canonical and non-canonical pathways according to whether it depends on the transcriptional co-activator β-catenin. The canonical Wnt/β-catenin pathway regulates the transcription of specific target genes and is closely associated with the control of cell proliferation and differentiation.¹⁸ By contrast, the non-canonical pathways are β-catenin-independent and mainly include the Wnt/planar cell polarity (PCP) pathway, which regulates tissue polarity and directional cell movement,¹⁹ and the Wnt/Ca2+ pathway, which is involved in early developmental processes and inflammatory regulation.^20,21

The canonical Wnt/β-catenin pathway is mediated by a defined set of ligands, receptors, and intracellular regulators. Secreted Wnt ligands bind to Frizzled (Fzd) receptors together with the co-receptors low-density lipoprotein receptor-related proteins 5/6 (LRP5/6). The β-catenin is the central effector, and its abundance is controlled by the “destruction complex”, which includes Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), and casein kinase 1α (CK1α). Other key components include Dishevelled (DVL), the E3 ubiquitin ligase adaptor β-transducin repeat-containing protein (β-TRCP), protein phosphatase 2A (PP2A), and nuclear T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors. Mammals possess 19 WNT genes encoding cysteine-rich, lipid-modified glycoproteins. Several ligands (eg, WNT1, WNT3A, WNT4, WNT7B, WNT8A, WNT10B, and WNT16) strongly activate canonical Wnt/β-catenin signaling.¹⁹ After secretion, Wnt ligands act in an autocrine and/or paracrine manner.²² Pathway activation requires ligand binding to both Fzd and LRP5/6 on the plasma membrane.¹⁵ Fzd receptors are seven-transmembrane proteins that recognize Wnts through a conserved extracellular N-terminal cysteine-rich domain (CRD).²³ Ligand binding promotes receptor complex formation and conformational changes,²⁴ leading to recruitment and activation of DVL at the membrane. Activated DVL inhibits the destruction complex, allowing β-catenin to escape phosphorylation and degradation. Stabilized β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it binds TCF/LEF factors to drive transcription of Wnt target genes. In the absence of Wnt ligands, the destruction complex phosphorylates β-catenin, which is then recognized by β-TRCP and targeted for ubiquitination and proteasomal degradation.²⁵ As a result, cytoplasmic β-catenin remains low and Wnt-responsive genes are kept inactive (Figure 1).

Figure 1.

Overview of the canonical Wnt/β‑catenin signaling pathway. In the OFF state (absence of Wnt ligands), β‑catenin is sequestered in the destruction complex and phosphorylated by GSK‑3, CK‑1α, APC, and axin, which targets it for ubiquitination and proteasome‑mediated degradation. In the ON state (presence of Wnt stimulation), the destruction complex is inhibited/disassembled, allowing β‑catenin to accumulate in the cytoplasm and translocate into the nucleus, where it partners with TCF/LEF to activate transcription of Wnt target genes.

Because Wnt signaling is highly interconnected and exhibits extensive crosstalk with other pathways, its precise contribution to diabetic complications has not been fully clarified. In view of this, the present review aims to provide a comprehensive overview of the mechanisms underlying the involvement of Wnt/β-catenin signaling in diabetic complications and to assess its therapeutic potential as a target for intervention. We also summarize recent progress in pathway-modulating strategies and discuss the principal obstacles to their clinical application.

Wnt/β-Catenin and Diabetic Complications

Wnt/β-Catenin and Diabetic Nephropathy

Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus (DM) and often progresses to end-stage renal disease.^26–28 Clinically, DN is characterized by persistent albuminuria, a progressive decline in glomerular filtration rate, and an increased risk of cardiovascular events.^26–28 Histopathologically, it is marked by glomerular basement membrane thickening, mesangial expansion driven by extracellular matrix (ECM) accumulation and mesangial cell proliferation, podocyte injury, and ultimately glomerulosclerosis and tubulointerstitial fibrosis. The development and progression of DN are multifactorial and involve chronic hyperglycemia, hemodynamic alterations, oxidative stress, inflammation, and profibrotic signaling. Notably, DN affects up to 40% of patients with diabetes;²⁹ although its incidence in type 1 diabetes (T1DM) has declined, the number of new cases in type 2 diabetes (T2DM) increased markedly between 1990 and 2017.²⁹

The Wnt/β-catenin pathway plays a critical role in DN, particularly in MC dysfunction, podocyte injury, and tubular cell damage.^12,30,31 Wnt/β-catenin signaling is linked to renal interstitial fibrosis and glomerulosclerosis. High glucose (HG) activates this pathway, with multiple canonical Wnt ligands and β-catenin upregulated in kidneys of both T1DM and T2DM animal models.³² HG also activates Wnt/β-catenin signaling in primary human renal proximal tubular epithelial cells (HRPTCs), while a monoclonal antibody targeting LRP6 blocked Wnt signaling and ameliorated DN by reducing renal inflammation, fibrosis, and albuminuria.³² Many studies report that overactivation of Wnt/β-catenin is associated with DN progression,^33–35 whereas others show that suppression of Wnt/β-catenin also contributes to renal injury and fibrosis.^36–39

Wnt/β-Catenin and Mesangial Cell Injury in DN

Mesangial cells (MCs) provide structural support for the glomerular capillary tuft, maintain the mesangial matrix, secrete soluble factors, and regulate capillary flow through contractility.³⁷ MC injury is a key contributor to DN⁴⁰ and is associated with HG-induced proliferation, apoptosis, inflammatory cytokine infiltration, and ECM accumulation.^41,42 HG has been reported to induce MC apoptosis and fibrosis by downregulating Wnt/β-catenin signaling.^36,38,43 Lin et al showed that HG reduced Wnt4/Wnt5a and nuclear β-catenin expression while increasing caspase-3 activity and MC apoptosis.³⁶ Overexpression of β-catenin attenuated HG-induced caspase-3 activation, PARP cleavage, and apoptosis.^36,44 In STZ-induced diabetic rats, GSK-3β inhibitors (BIO) and simvastatin restored Wnt/β-catenin signaling and reversed diabetes-induced MC apoptosis,^36,44 indicating that β-catenin stability is crucial for MC homeostasis.

Oxidative stress also contributes to MC injury. Lin et al showed that HG‑induced oxidative stress promotes apoptosis by suppressing Wnt/β‑catenin signaling.³⁷ Specifically, HG activates Ras/Rac1, increases reactive oxygen species, activates GSK‑3β, and inhibits Wnt/β‑catenin signaling, leading to caspase‑3 activation and PARP cleavage.³⁷ Superoxide‑mediated β‑catenin destabilization further aggravates apoptosis in HG‑stressed MCs. Wnt/β‑catenin signaling also modulates TGF‑β1–driven fibrosis in MCs.³⁸ HG elevates TGF‑β1 and fibronectin expression concomitant with Wnt/β‑catenin downregulation.³⁸ Restoring β‑catenin attenuates HG‑induced, c‑Jun–mediated TGF‑β1 fibrosis, and GSK‑3β inhibition (BIO or SB216763) rescues β‑catenin levels and reduces fibrogenic gene expression in diabetic rats.³⁸

In contrast, other reports suggest that Wnt/β-catenin activation drives DN by promoting MC proliferation, apoptosis, and ECM accumulation. Wnt/β-catenin activation has been observed in renal tissue from STZ-induced diabetic rats.⁴⁵ HG induces multiple Wnt ligands, activates Wnt/β-catenin signaling, and increases β-catenin in glomerular MCs.⁴⁶ Blocking this pathway alleviates DN progression by reducing HG-induced proliferation and ECM accumulation.^45–47 Chen et al further showed that β-catenin overexpression increased MC apoptosis.⁴⁷ These discrepancies may reflect differences in experimental models, disease stage, or the magnitude/duration of pathway activation. Overall, Wnt/β-catenin seems to act in a dose- and context-dependent manner: moderate activation may be protective, whereas sustained or excessive activation promotes injury.

Wnt/β‑Catenin and Podocyte Dysfunction in DN

Podocytes cover the outer surface of the glomerular basement membrane (GBM) and, together with glomerular endothelial cells and the GBM, form the glomerular filtration barrier (GFB), which is essential for restricting protein filtration.⁴⁸ In DN, podocyte injury is widely recognized as a primary driver of impaired filtration and proteinuria.⁴⁹ Evidence suggests that both insufficient and excessive β‑catenin activity can damage podocytes, indicating a dual, context‑dependent role for Wnt/β‑catenin signaling.

In vitro studies show that Wnt/β‑catenin signaling regulates podocyte motility, adhesion, apoptosis, and differentiation.⁵⁰ Appropriate β‑catenin levels are required for normal podocyte function,⁵¹ whereas excessive activation contributes to podocyte dysfunction in DN.^33,50 Increased Wnt1, Wnt2b, Wnt4, Wnt16, and nuclear β‑catenin have been observed in podocytes from patients and mouse models of DN.⁵⁰ Pharmacologic activation of β‑catenin induces foot process effacement and albuminuria in wild‑type mice but not in β‑catenin–knockout mice.⁵⁰ In a podocyte‑injury model with proteinuria, in vivo Wnt1 overexpression worsened albuminuria, whereas Dickkopf‑1 (DKK1)–mediated inhibition of Wnt/β‑catenin restored podocyte function and reduced albuminuria.³³ These findings implicate Wnt/β‑catenin activation in podocyte injury and proteinuria.

Earlier work showed that HG activates Wnt/β‑catenin signaling in podocytes.^33,52 This may occur through increased Wnt ligands or stabilized β‑catenin, leading to transcription of downstream targets. Reported targets include Snail1, lymphoid enhancer‑binding factor 1 (LEF1), plasminogen activator inhibitor‑1 (PAI‑1), fibroblast‑specific protein‑1 (FSP‑1), α‑smooth muscle actin (α‑SMA), matrix metalloproteinase‑9 (MMP‑9), the renin–angiotensin system (RAS), and transient receptor potential cation channel 6 (TRPC6).^53,54 Podocyte epithelial–mesenchymal transition (EMT) correlates with proteinuria and renal fibrosis in DN.^33,55 Wnt/β‑catenin activation induces Snail, which promotes EMT by repressing E‑cadherin and inducing inhibitor of differentiation 1.^33,56 LEF1 interacts with β‑catenin and reinforces Wnt signaling through a positive‑feedback loop.⁵⁷ Increased EMT markers (PAI‑1, FSP‑1, MMP‑9) have been detected in podocytes from patients and mouse models of DN.^55,58 PAI‑1, a direct Wnt/β‑catenin target, may mediate fibrogenic effects.⁵⁹ Although the role of MMPs in podocyte injury is not fully defined, they may promote shedding of slit diaphragm (SD)–associated proteins.⁶⁰ Notably, Wnt/β-catenin activation may contribute to podocyte injury by inducing intrarenal RAS components. Zhou et al showed that several RAS genes, including AGT, renin, ACE, AT1, and AT2, are direct targets of Wnt/β-catenin signaling, and that inhibition of this pathway suppressed RAS activation and ameliorated proteinuria and renal injury.⁵³ More recently, Sirtuin 6 was found to protect podocytes by inhibiting the Wnt1/β-catenin pathway and blocking RAS activation.⁶¹ These findings further support an important role of the Wnt/β-catenin-RAS axis in podocyte dysfunction.

Several downstream effectors of Wnt/β-catenin signaling, including Snail1, MMPs, FSP‑1, and PAI‑1, also promote cell migration.^62–64 Increased podocyte migration weakens adhesion to the GBM and favors detachment. Wnt/β‑catenin signaling also reduces podocyte viability by activating TRPC6, a key calcium‑permeable channel. TRPC6 activation causes excessive calcium influx, leading to foot process effacement, podocyte apoptosis, and glomerular injury.⁶⁵ β‑Catenin can also promote ubiquitin‑mediated degradation of Wilms’ tumor 1 (WT1), leading to podocyte dedifferentiation and mesenchymal transition.⁶⁶ WT1 is essential for maintaining the differentiated state of adult podocytes and drives expression of podocyte‑specific genes such as nephrin and podocalyxin.^67–69 Another study reported that Wnt/β‑catenin activation upregulates ubiquitin carboxy‑terminal hydrolase 1 (UCH‑L1), enhancing podocyte migration and disrupting key proteins.⁵² Additional evidence indicates that Wnt/β‑catenin activation compromises SD integrity by suppressing key SD proteins^33,66 Nephrin and podocalyxin are major SD components required for GFB integrity.⁷⁰ Nephrin‑knockout mice develop mild proteinuria, foot process effacement, slit narrowing, and podocyte apoptosis.⁷¹ In podocytes, Wnt/β‑catenin–mediated nephrin suppression appears to occur via Snail induction and WT1 repression.^33,66 Snail1 directly represses nephrin, whereas WT1 promotes nephrin and podocalyxin transcription.^68,69

Conflicting results have also been reported. Podocyte‑specific β‑catenin knockout mice and mice with podocyte‑specific DKK1 overexpression showed increased albuminuria and mesangial expansion compared with STZ‑induced diabetic controls.⁵⁰ Conversely, mice expressing stabilized β‑catenin in podocytes developed early GBM alterations followed by later albuminuria and greater susceptibility to glomerular injury.⁵⁰ These findings suggest that both inhibition and activation of Wnt/β‑catenin can exacerbate renal injury in DN. In cultured podocytes, β‑catenin deletion increased differentiation markers and adhesiveness but also heightened susceptibility to apoptosis,⁵⁰ implying that pathway inhibition may injure podocytes by promoting apoptosis. This contrasts with an adriamycin (ADR)‑induced podocyte‑injury model in which β‑catenin knockout or DKK1 treatment restored podocyte function and reduced albuminuria.^33,72 The discrepancy may reflect differences between chronic diabetic injury (15 weeks) and acute ADR injury (4 days). Overall, current evidence supports a dual, context-dependent role of Wnt/β-catenin signaling in podocyte regulation during DN.

Wnt/β‑Catenin and Renal Tubular Cell Injury in DN

Beyond podocytes and MCs, renal tubular cells are also central to the development of DN.⁷³ Tubular epithelial-to-EMT contributes to tubulointerstitial fibrosis, a characteristic pathological feature of DN and a common final pathway leading to end-stage renal failure. In cultured human renal proximal tubular cells (HRPTCs), HG increased cytosolic β‑catenin and activated Wnt/β‑catenin signaling.³² This activation induced the expression of downstream target genes such as Snail and Twist, promoted EMT, and upregulated mesenchymal markers including fibronectin, vimentin, and α‑SMA.⁷⁴ As key transcription factors involved in tubular EMT, Snail and Twist may mediate part of the profibrotic effect of Wnt/β-catenin activation.⁷⁵ Consistently, Lee et al showed that β‑catenin–specific siRNAs reversed HG‑induced EMT in tubular cells⁷⁶ supporting a direct role for Wnt/β‑catenin in this process. Tian et al further demonstrated that β‑catenin serves as a Smad cofactor in TGF‑β1–induced EMT of renal tubular epithelial cells.⁷⁷ Together, these findings support a direct role for β-catenin in tubular epithelial injury and EMT under diabetic conditions.

Wnt/β‑catenin signaling is also activated in proximal tubular epithelial cells in DN models in vitro and in vivo, accompanied by increased CTGF and fibronectin.³² Blocking LRP6 with a neutralizing antibody inhibited pathway activation and reduced ECM accumulation and proteinuria in DN animal models, implicating Wnt/β‑catenin in tubulointerstitial fibrosis.³² In addition, Ren et al reported that sitagliptin suppressed Wnt/β‑catenin signaling in DN and attenuated renal tubulointerstitial transdifferentiation and fibrosis.⁷⁸ Overall, these results suggest that β‑catenin activation is critical for tubular EMT and tubulointerstitial fibrosis in DN.

Recent studies have further expanded the mechanistic basis linking Wnt/β-catenin signaling to renal fibrosis. Hyperactivation of this pathway has been shown to induce renal fibrosis through microbial-derived tryptophan metabolism-mediated AhR signaling in both rodents and humans,⁷⁹ suggesting that gut-kidney metabolic signaling may amplify tubular injury and fibrosis through Wnt/β-catenin activation. In addition, m6A RNA methylation has been reported to drive kidney fibrosis by upregulating β-catenin signaling, indicating that epitranscriptomic regulation may contribute to sustained pathway activation.⁸⁰ Emerging evidence also suggests that myeloid-derived Wnts play an indispensable role in macrophage and fibroblast activation during kidney fibrosis,⁸¹ highlighting that Wnt/β-catenin-mediated fibrogenesis is not limited to tubular epithelial cells but also involves extensive intercellular communication within the renal microenvironment. Collectively, these findings broaden the current understanding of Wnt/β-catenin signaling from a pathway involved primarily in tubular EMT to a more integrated profibrotic signaling network in DN.

Wnt/β-catenin signaling appears to play a biphasic role in DN, and the seemingly contradictory findings across studies can be unified by a stage- and threshold-dependent model. In this model, Wnt/β-catenin activity operates within three functional ranges: a basal range that supports normal renal homeostasis, an intermediate adaptive range that may transiently protect renal cells during early diabetic stress, and a high or sustained range that becomes pathogenic. More specifically, when signaling remains near the basal level, insufficient activity may compromise cell survival and stress resistance in mesangial cells and podocytes; when signaling rises into an adaptive intermediate range, it may help preserve cellular integrity under short-term hyperglycemic stress; however, once activation exceeds a critical threshold or is maintained for a prolonged period, it promotes apoptosis, dedifferentiation, proliferation, extracellular matrix accumulation, epithelial–mesenchymal transition, and tubulointerstitial fibrosis. This framework helps explain why both reduced and excessive β-catenin activity have been associated with injury in different experimental settings. We therefore propose that the apparent discrepancy mainly reflects differences in disease stage, glucose burden, duration of exposure, cell type, and the amplitude and persistence of pathway activation rather than a true contradiction. In this sense, the threshold is not a fixed numeric value but a semiquantitative biological boundary that shifts with context. During early DN, short-term or moderate Wnt/β-catenin activation may be adaptive, whereas in established or advanced DN, prolonged activation exceeds the pathogenic threshold and accelerates fibrosis and structural damage. This interpretation is supported by the regulatory roles of endogenous Wnt antagonists such as DKK1, secreted frizzled-related proteins, and Klotho, as well as by cross-talk with TGF-β/Smad, oxidative stress, RAS, and inflammatory signaling, all of which can shift the transition point from protection to injury. Clinically, these observations suggest that therapeutic strategies should aim to restore Wnt/β-catenin signaling to an optimal range rather than indiscriminately blocking the pathway.

Wnt/β-Catenin and Diabetic Retinopathy

Diabetic retinopathy (DR) is a common ocular complication of DM and a leading cause of blindness and visual impairment in adults.^82,83 It is a chronic and progressive retinal microvascular disorder characterized by persistent neurovascular dysfunction, breakdown of the blood-retinal barrier, and retinal inflammation and oxidative stress induced by long-term hyperglycemia.^84,85 Clinically, DR is usually classified into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). NPDR is the early stage and is characterized by increased capillary permeability, microaneurysms, retinal hemorrhages, hard exudates, cotton-wool spots, macular ischemia, and macular edema.⁸⁶ PDR represents the advanced stage and is marked by pathological retinal neovascularization, which may lead to vitreous hemorrhage, tractional retinal detachment, and severe vision loss.⁸⁷ The global prevalence of DR among people with diabetes is estimated to be approximately 20–35%,^82,83 underscoring its substantial disease burden. Taken together, these features suggest that DR is a complex retinal disorder involving not only microvascular injury, but also inflammatory and neurodegenerative changes.

Aberrant activation of Wnt/β-catenin signaling has been implicated in diabetic retinopathy (DR).^88,89 β-Catenin levels are increased in retinal sections from patients with NPDR compared with non-diabetic controls.⁸⁸ In experimental models, β-catenin and LRP5/6 are elevated in Akita mice and STZ-induced diabetic rats, which represent NPDR-like changes, as well as in oxygen-induced retinopathy, a model of proliferative retinopathy.⁸⁸ These findings support activation of the Wnt/β-catenin pathway across different stages of DR. Consistently, serum and vitreous DKK-1 levels are reduced in patients with DR compared with non-diabetic or non-DR subjects.⁹⁰ Because DKK-1 is an endogenous antagonist of Wnt/β-catenin signaling, its reduction may favor pathway overactivation; correspondingly, intravitreal DKK-1 suppresses retinal inflammation, vascular leakage, and neovascularization in DR animal models.⁸⁸

Although DR is the most common Wnt-related ocular disease, the underlying mechanisms remain incompletely defined. Current evidence indicates that Wnt/β-catenin signaling does not act in isolation, but rather interacts with multiple pathogenic pathways involved in oxidative stress, angiogenesis, inflammation, vascular leakage, and EMT-like changes in retinal tissue. Through this crosstalk, Wnt/β-catenin appears to function as an important signaling hub in DR, integrating metabolic stress with downstream vascular and inflammatory responses.

Wnt/β‑Catenin and Oxidative/Nitrosative Stress

Chronic hyperglycemia induces oxidative stress, contributing to early retinal neuronal injury,⁹¹ pericyte loss, blood‑retinal barrier disruption, increased vascular permeability, and progression to advanced DR.^92–94 In bovine retinal capillary endothelial cells, aminoguanidine prevented the HG‑induced rise in nuclear β‑catenin, indicating that oxidative stress can activate Wnt/β‑catenin signaling.⁸⁸ Likewise, N‑acetyl‑cysteine lowered retinal β‑catenin levels in diabetic rats.⁹⁵ Nitrosative stress appears to act similarly: in adult retinal pigment epithelium (ARPE) cells, HG‑driven nitrosative stress activated Wnt/β‑catenin, while its inhibition suppressed pathway activity.⁹⁶ Uric acid, a peroxynitrite scavenger, reduced diabetes‑induced Wnt/β‑catenin activation and diminished retinal inflammation and vascular leakage in perfused diabetic rat retinas.⁹⁶

Evidence also points to feedback regulation. DKK1 blocked HG‑induced ROS generation,⁸⁸ suggesting Wnt/β‑catenin can, in turn, promote oxidative stress. Liu et al showed that HG upregulated Nox2 and Nox4, thereby increasing ROS production and activating Wnt/β‑catenin; pathway activation then downregulated SOD1 and SOD2, further aggravating oxidative burden.⁹⁷ Taken together, these findings support a bidirectional relationship in the diabetic retina, in which oxidative/nitrosative stress activates Wnt/β-catenin, while Wnt/β-catenin signaling amplifies oxidative stress, thereby creating a feed-forward loop. However, relative to oxidative stress pathways that directly mediate hyperglycemia-induced injury, Wnt/β-catenin may be better understood as an amplifying and coordinating mechanism rather than the sole initiating event.

Wnt/β‑Catenin and Retinal Neovascularization

Wnt/β‑catenin signaling is a key regulator of retinal vascular development and contributes to pathological angiogenesis in retinopathy.⁹⁸ LRP5‑deficient mice show delayed and incomplete retinal vascularization,⁹⁸ highlighting the physiological importance of this pathway in retinal vessel formation. In DR, VEGF remains the central and best-established angiogenic factor, and its level in aqueous humor increases with disease severity.^99,100 Notably, VEGF has also been identified as a downstream target of Wnt/β-catenin signaling.¹⁰¹ In ARPE cells, pathway activation increases VEGF and ICAM‑1 expression.⁹⁶ In DR models, Wnt/β‑catenin activation elevates VEGF, whereas pathway inhibition reduces VEGF levels.⁸⁸ Consistently, intravitreal DKK1 reduces VEGF, MMP2, and MMP9, suppresses neovascularization, and improves retinal function in DR rats by blocking Wnt/β‑catenin signaling.¹⁰²

These observations suggest that the proangiogenic effect of Wnt/β-catenin is mediated, at least in part, through the VEGF axis rather than through a completely independent mechanism. Therefore, compared with VEGF alone, Wnt/β-catenin may function more as an upstream regulatory pathway that modulates VEGF expression together with other angiogenic and inflammatory mediators. This broader regulatory role may explain why inhibition of Wnt/β-catenin in experimental models affects not only neovascularization but also vascular leakage and inflammation. Nevertheless, the quantitative contribution of Wnt/β-catenin relative to VEGF-dominant signaling in human DR remains to be fully clarified.

Wnt/β‑Catenin and Inflammation

DR is a chronic, low‑grade inflammatory disorder, and inflammation is pivotal to its development.^103,104 Retinal inflammation involves activation of macrophages, microglia, and Müller cells, accompanied by increased IL‑1β, TNF‑α, and MCP‑1.^103,104 Aqueous humor levels of IL‑8, MCP‑1, and VEGF are higher in diabetic eyes,¹⁰⁵ and vitreous levels of endothelin‑1, syndecan‑1, PlGF, ANGPTL‑4, TNF‑α, IL‑6, IL‑8, and VEGF rise in PDR.^106,107 Elevated TNF‑α, IL‑1β, and ICAM‑1 promote leukocyte‑endothelial adhesion and leukostasis, disrupt the BRB, and drive apoptosis and capillary leakage.^92,108 TNF‑α, VEGF, and ICAM‑1 are also Wnt/β‑catenin target genes linked to DR‑related inflammation.^88,109 In ARPE cells, pathway activation increases VEGF and ICAM‑1, whereas inhibition lowers their expression and mitigates vascular permeability and inflammation in diabetic retinas.⁹⁶ Blocking LRP6 with Mab2F1 likewise reduces VEGF, ICAM‑1, and TNF‑α and improves vascular leakage and inflammation in DR models.¹¹⁰

Overall, these findings indicate that Wnt/β-catenin activation aggravates retinal inflammation by upregulating multiple inflammatory and permeability-related mediators. Compared with single downstream effectors such as VEGF, Wnt/β-catenin appears to have a broader regulatory scope because it simultaneously influences angiogenic, inflammatory, and barrier-disruptive responses. However, current evidence is still derived largely from experimental studies, and the relative quantitative importance of Wnt/β-catenin compared with other inflammatory pathways in clinical DR has not yet been precisely established.

Beyond its direct effects on oxidative stress, angiogenesis, and inflammation, Wnt/β-catenin signaling also exhibits extensive crosstalk with other major pathogenic pathways in DR, further broadening its impact on disease progression.

Wnt/β-Catenin Crosstalk with VEGF, NF-kB, and TGF-β Pathways in DR

In DR, Wnt/β-catenin signaling does not function in isolation, but interacts with multiple pathogenic pathways involved in angiogenesis, inflammation, and tissue remodeling. Among these, its relationship with the VEGF, NF-κB, and TGF-β pathways appears particularly relevant. Importantly, from a comparative perspective, the VEGF axis remains the best established and most direct effector pathway in DR, especially in relation to retinal vascular leakage, macular edema, and neovascularization. By contrast, Wnt/β-catenin is more likely to function as an upstream or network-level regulator that influences several downstream responses, including VEGF expression as well as inflammatory and fibrotic signaling.

The interaction between Wnt/β-catenin and the VEGF axis is the best characterized. VEGF is a central driver of retinal vascular leakage and pathological neovascularization in DR, and substantial evidence indicates that it is a downstream target of Wnt/β-catenin signaling.^89,94 In diabetic retinas and retinal cells, activation of Wnt/β-catenin increases VEGF expression, whereas pathway inhibition reduces VEGF levels and attenuates vascular leakage and neovascular responses.^88,96,102 These findings indicate that part of the pathogenic role of Wnt/β-catenin in DR is mediated through the VEGF axis. However, current evidence suggests that VEGF contributes more directly to angiogenic manifestations, whereas Wnt/β-catenin exerts broader but less immediate regulatory effects.

Wnt/β-catenin signaling also interacts with inflammatory signaling, particularly the NF-κB pathway. DR is characterized by chronic low-grade inflammation with increased expression of TNF-α, IL-1β, MCP-1, and ICAM-1.^103,104,108 Several of these mediators are upregulated in association with Wnt/β-catenin activation,^88,96,109 suggesting convergence between Wnt-dependent and NF-κB-dependent inflammatory programs. As NF-κB is a central regulator of inflammatory gene transcription, its role in inflammatory injury is likely more direct, whereas Wnt/β-catenin may help amplify or sustain this inflammatory environment.

Potential crosstalk between Wnt/β-catenin and TGF-β signaling may also be relevant, particularly in advanced DR. TGF-β is a key mediator of extracellular matrix accumulation, tissue remodeling, and fibrosis, and may contribute to epithelial- or endothelial–mesenchymal transition-like changes in the diabetic retina.¹¹¹ Although direct evidence in DR remains limited, the functional overlap between Wnt/β-catenin and TGF-β pathways in other diabetic and fibrotic disorders suggests that their interaction may be more relevant to fibrovascular membrane formation and late-stage structural remodeling than to early vascular dysfunction.

Overall, current evidence suggests that Wnt/β-catenin is unlikely to replace the VEGF axis as the principal effector pathway in DR, but may serve as a broader coordinating signal linking angiogenesis with inflammatory and remodeling processes. This network-level role may explain why inhibition of Wnt/β-catenin in experimental models can simultaneously reduce VEGF expression, inflammation, vascular leakage, and neovascularization. Nevertheless, its relative contribution compared with the VEGF axis and other major pathways still requires further clarification, particularly in human DR.

Wnt/β‑Catenin and Diabetic Cutaneous Ulcers

Diabetic cutaneous ulcers (DCU) are a frequent and severe complication of diabetes. Nearly one in four patients may develop foot or skin ulcers, and about 18.6 million people worldwide are affected each year.¹¹² Among those with diabetic foot ulcers, around 20% eventually require lower‑extremity amputation, either minor or major.¹¹³ The pathogenesis of DCU is multifactorial and still not fully defined. Long‑term hyperglycemia leads to peripheral neuropathy, peripheral vascular disease, oxidative stress, and immune dysfunction.¹¹⁴ These changes weaken neuroprotective mechanisms, reduce blood flow and nutrient delivery, and interfere with normal wound repair, making ulcers chronic and difficult to heal. Normally, wound healing proceeds through inflammation, proliferation, and remodeling,¹¹⁵ but in diabetes this sequence is disrupted. Diabetic wounds often remain in a prolonged inflammatory state, show limited cellular proliferation, and exhibit abnormal remodeling with loss of essential structural proteins and regulatory factors.¹¹⁶

Wnt/β‑catenin signaling is involved in wound repair, angiogenesis, epithelial remodeling, and stem‑cell maintenance.⁸ Diabetes can impair this pathway. In diabetic ulcer model rats, β‑catenin and Rspo‑3 levels were reduced in wound tissue, while GSK‑3β was increased compared with controls, indicating suppressed Wnt/β‑catenin activity. This down‑regulation may contribute to delayed healing in diabetic ulcers.¹¹⁷

Wnt/β‑Catenin and Wound Inflammation

A controlled inflammatory response helps clear pathogens, but diabetic wounds often show excessive and prolonged inflammation. Accumulation of advanced glycation end products (AGEs) impairs neutrophil phagocytosis of bacteria and debris, while large numbers of monocytes are recruited and differentiate into macrophages. This results in overproduction of TNF‑α, IL‑1β, and IL‑6, maintaining inflammation and hindering subsequent proliferation and re‑epithelialization.¹¹⁸

Inflammation is the first phase of wound repair and is essential for tissue regeneration. Immediately after injury, inflammatory cells are recruited to the wound site to remove pathogens and cellular debris and to initiate the healing response.^119,120 Neutrophils are among the earliest infiltrating cells and play a central role in antimicrobial defense, whereas monocytes/macrophages subsequently contribute to debris clearance and secrete cytokines, chemokines, and growth factors that promote angiogenesis, fibroblast activation, and re-epithelialization. Under normal conditions, this inflammatory response is tightly regulated and gradually resolves, allowing the wound to enter the proliferative phase.^119,120 In contrast, persistent or excessive inflammation disrupts this transition and is a hallmark of chronic non-healing wounds, including diabetic cutaneous ulcers. Wnt signaling is closely involved in this process through its regulation of inflammatory cell activity, tissue repair, and the progression from inflammation to regeneration. Wnt signaling is closely involved in this process. Macrophages are a major source of Wnt ligands during healing, and their dysfunction is a key driver of the inflammatory response.¹²¹ Evidence indicates crosstalk between macrophages and the Wnt/β-catenin pathway, with Wnts shaping macrophage polarization.¹²² Abaricia et al reported that Wnt3a and Wnt5a favor pro-inflammatory M1 polarization and increase IL-1β, IL-12, and TNF-α, whereas Wnt5b and Wnt11 promote an anti-inflammatory M2 phenotype and enhance IL-4 and IL-10 secretion.¹²¹ Recent studies showed that asiaticoside nitric oxide gel and Ruyi Jinhuang Powder reduce IL-8, IL-1β, and TNF-α and alleviate DCU inflammation by activating Wnt/β-catenin signaling.^123,124 Collectively, these observations indicate that Wnt/β-catenin signaling participates in inflammatory regulation during wound healing by modulating macrophage phenotype and cytokine production.

Wnt/β‑Catenin and the Proliferative Phase of Wound Healing

After the inflammatory phase, DCU wounds enter the proliferative stage, when fibroblasts, epidermal stem cells, endothelial cells and keratinocytes actively proliferate, migrate and differentiate to rebuild tissue. Growth factors such as FGF, EGF, NGF, and PDGF coordinate activation of repair cells.¹²⁵ Fibroblasts produce collagen and extracellular matrix to form granulation tissue, while keratinocyte proliferation covers the wound surface and supports re‑epithelialization.¹²⁶ Wnt/β‑catenin signaling is a key regulator of this stage.

In diabetic wounds, the Wnt/β‑catenin pathway is suppressed. Yang et al observed lower β‑catenin levels in diabetic rat wounds than in controls.¹²⁷ Activation of this pathway promotes fibroblast growth, epidermal cell proliferation, keratinocyte differentiation and migration, and hair follicle regeneration, thereby improving repair.^128,129 For example, exogenous LRG1 restores proliferation, migration and tube formation of HUVECs under hyperglycemic conditions by activating Wnt/β‑catenin, which accelerates diabetic wound healing.¹²⁷ Ruyi Jinhuang Powder likewise enhances healing in diabetic mice by stimulating fibroblast proliferation and migration through this pathway.¹²⁴

Wnt/β‑catenin signaling also increases expression of pro‑healing growth factors. Asiaticoside nitric oxide gel raises VEGF levels via Wnt/β‑catenin activation.¹²³ VEGF drives endothelial proliferation and neovascularization, improving oxygen and nutrient delivery and clearing metabolic waste, thus creating a favorable microenvironment for repair.¹³⁰ Quercetin similarly elevates VEGF and FGF and promotes cutaneous wound healing via Wnt/β‑catenin signaling.¹³¹ Overall, regulation of Wnt/β‑catenin during the proliferative phase is complex and involves extensive interaction with other signaling pathways.

Wnt/β‑Catenin Signaling and Wound Remodeling

The remodeling stage marks the completion of wound repair. At this time, fibroblasts differentiate into myofibroblasts that contract the wound edges and release matrix metalloproteinases (MMPs) to reorganize the extracellular matrix, replacing collagen III with the stronger collagen I.¹³² Tissue inhibitors of metalloproteinases (TIMPs) are produced to limit excessive matrix breakdown.¹³³ Wound contraction driven by myofibroblasts is therefore critical for closure.¹³⁴

Wnt/β‑catenin signaling promotes the fibroblast‑to‑myofibroblast transition. Pathway activation increases α‑SMA expression, encouraging differentiation and accelerating contraction.¹³¹ In diabetes, this pathway is weakened, β‑catenin stability and nuclear translocation are impaired, and remodeling‑related genes such as MYC, CCND1, and MMPs are down‑regulated.¹³⁵ Wnt/β‑catenin also interacts with other signaling systems during diabetic wound repair, including crosstalk with Notch and cooperation with the TGF‑β/Smad pathway.⁸

Wnt/β‑Catenin Signaling and Diabetic Cardiovascular Complications

Cardiovascular disease remains the main cause of death in patients with diabetes. Common complications include diabetic cardiomyopathy, myocardial fibrosis, atherosclerosis, and heart failure.¹³⁶ A growing body of evidence points to the Wnt/β‑catenin pathway as an important contributor to these disorders. Depending on the disease stage and tissue context, aberrant activation or suppression of Wnt/β‑catenin can drive cardiomyocyte injury, fibrosis, oxidative stress, inflammation, and metabolic imbalance.^137–140

Wnt/β‑Catenin Signaling and Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) is a diabetes-related myocardial disorder that occurs independently of hypertension and coronary artery disease. It is characterized by early diastolic dysfunction, followed by systolic impairment, cardiomyocyte hypertrophy, and interstitial fibrosis, and may eventually progress to heart failure.¹⁴¹ DCM is now widely regarded as a multifactorial process involving metabolic disturbance, oxidative stress, inflammation, mitochondrial dysfunction, impaired autophagy, and extracellular matrix remodeling. Within this context, Wnt/β-catenin signaling has emerged as an important pathway linking cellular stress to structural and functional changes in the diabetic heart.^137–139

Activation of Wnt/β-catenin signaling has been documented in both type 1 and type 2 diabetic models. In type 1 diabetic mice, myocardial Wnt signaling is enhanced together with increased β-catenin accumulation,¹³⁸ while STZ-induced diabetic rats show progressive upregulation of Wnt2, β-catenin, c-Myc, and phosphorylated GSK3beta over 12 weeks.¹³⁷ Chronic hyperglycemia disrupts mitochondrial homeostasis and increases ROS production, which may inhibit GSK3β activity, reduce β-catenin degradation, and facilitate its cytoplasmic accumulation and nuclear translocation.¹⁴² Activated β-catenin then promotes downstream transcriptional programs associated with cardiomyocyte stress and hypertrophic remodeling, partly through interaction with c-Myc.¹⁴²

Evidence also suggests that Wnt/β-catenin signaling contributes directly to changes in cardiomyocyte phenotype. In neonatal rat cardiomyocytes, both high glucose and Wnt3a increase β-catenin levels and induce hypertrophic responses, including upregulation of atrial natriuretic peptide (ANP).¹³⁸ Methazolamide attenuates these changes by stabilizing the AXIN1-β-catenin destruction complex, thereby promoting β-catenin degradation and reducing myocardial hypertrophy in type 1 diabetic mice.¹³⁰ In a type 2 diabetes model induced by STZ combined with a high-fat diet, myocardial β-catenin and TCF7L2 expression are likewise increased, and Wnt/β-catenin signaling promotes carbonic anhydrase 2 (CA2) expression through TCF7L2, contributing to cardiac dysfunction.¹⁴³ Inhibition of the β-catenin/TCF7L2 interaction with iCRT14 prevents high-glucose-induced cardiomyocyte enlargement in vitro and improves cardiac function in diabetic mice.¹⁴³

Autophagy may represent another key link between Wnt/β-catenin activation and diabetic cardiac injury. Under physiological conditions, autophagy maintains protein turnover and mitochondrial quality control in cardiomyocytes, whereas diabetes suppresses this protective mechanism. Activation of Wnt/β-catenin signaling inhibits GSK3β, enhances mTOR signaling, and restrains autophagy initiation, thereby promoting the accumulation of damaged organelles and further ROS generation. This may establish a vicious cycle in which mitochondrial dysfunction activates β-catenin signaling, while β-catenin activation further impairs mitochondrial quality control and aggravates cellular stress. Consistent with this idea, 1.25-dihydroxyvitamin D3 restores autophagy through the β-catenin/GSK3β/mTOR axis and alleviates hypertrophy and interstitial fibrosis in diabetic rats.¹⁰ Overall, current evidence supports a role for Wnt/β-catenin signaling in the development of DCM through its effects on hypertrophy, autophagy impairment, and ventricular remodeling.

Wnt/β-Catenin Signaling and Diabetic Myocardial Fibrosis

Diabetic myocardial fibrosis (DMF) is a major pathological feature of DCM and results from sustained cardiomyocyte injury, fibroblast activation, and excessive ECM deposition.¹⁴⁴ It is a central determinant of myocardial stiffness, impaired relaxation, and progressive cardiac dysfunction. Increasing evidence indicates that Wnt/β-catenin signaling is involved in this fibrotic process by influencing both fibroblast activity and matrix remodeling.

Clinical and experimental studies have linked myocardial fibrosis with increased MMP activity and dysregulated ECM turnover.¹⁴⁵ In KKAy diabetic mice, cardiac fibrosis is accompanied by elevated expression of Wnt1,β-catenin, MMP7, and fibronectin, suggesting activation of a profibrotic Wnt/β-catenin program.¹⁴⁶ Tangshen Formula ameliorates fibrosis in this model by suppressing Wnt/β-catenin signaling and reducing MMP7 and fibronectin expression.¹⁴⁶ These findings indicate that β-catenin contributes not only to fibroblast activation but also to fibronectin accumulation and matrix reorganization in the diabetic myocardium.

The profibrotic effect of Wnt/β-catenin signaling is also closely related to its interaction with other signaling pathways, particularly TGF-β1/Smad. Both pathways converge on fibroblast activation, ECM synthesis, and tissue stiffening.¹⁴⁷ In KKAy mice, Tangshen Formula increases Smad7 expression, inhibits TGF-β/Smad2/3 signaling, and enhances Smurf2-mediated ubiquitination and degradation of β-catenin, thereby suppressing both profibrotic pathways.¹⁴⁶ This suggests that Wnt/β-catenin and TGF-β/Smad signaling may act in concert to promote chronic matrix deposition and fibrotic progression in the diabetic heart. In addition, exogenous spermine has been shown to attenuate myocardial fibrosis in diabetic rats by inhibiting endoplasmic reticulum stress and Wnt/β-catenin signaling, further supporting the view that β-catenin participates in a broader stress-fibrosis network.

Taken together, a cardiac systems model of diabetic cardiovascular injury can be proposed in which hyperglycemia and lipid overload initiate mitochondrial dysfunction, ROS accumulation, and inflammatory stress; these changes activate Wnt/β-catenin signaling in cardiomyocytes and fibroblasts, leading to hypertrophy, impaired autophagy, fibroblast activation, and maladaptive ECM remodeling. Through its interactions with mTOR, TCF7L2, MMP-related matrix turnover, and TGF-β/Smad signaling, β-catenin helps couple early metabolic injury to later structural remodeling and functional decline. This integrative role makes Wnt/β-catenin a potentially important therapeutic target in both DCM and DMF.

Wnt/β‑Catenin Signaling and Diabetic Neuropathy

Diabetic neuropathy is one of the most common chronic complications of diabetes and represents a heterogeneous spectrum of peripheral nerve disorders resulting from chronic hyperglycemia and associated metabolic abnormalities.^148,149 Clinically, it commonly manifests as pain, numbness, paresthesia, burning sensations, or sensory loss, often beginning in the distal extremities and progressing in a length-dependent manner. In more advanced cases, motor dysfunction, foot deformity, and ulceration may occur. Multiple pathogenic mechanisms have been implicated in diabetic neuropathy, including oxidative stress, inflammation, mitochondrial dysfunction, impaired neurotrophic support, and diabetes-related microvascular injury, all of which contribute to neuronal dysfunction and progressive nerve fiber loss.^148–151 Among these subtypes, DPN is the predominant clinical form, commonly manifesting as sensory loss, pain, burning, tingling, or numbness.¹⁵² DPN is characteristically length-dependent, usually starting in the toes and feet and then progressing proximally; once it reaches the calves, the hands and fingers may also be affected.¹⁵³ Both large myelinated fibers and small unmyelinated or thinly myelinated fibers can be involved. Demyelination is a typical pathological change in DPN and is closely associated with nerve dysfunction and reduced regenerative capacity.¹⁵⁴ The prevalence of DPN is high, affecting about 50% of patients with type 1 or type 2 diabetes and roughly 30% of those with prediabetes.¹⁵⁵ Proposed mechanisms include hyperglycemia‑induced cytokines, AGEs accumulation, chemokines, PKC activation, mitochondrial dysfunction, NF-κB activation, endoplasmic reticulum (ER) stress, and oxidative damage.^154,156 Increasing evidence shows that abnormal activation or suppression of Wnt/β‑catenin signaling contributes to DPN, making this pathway a focus of current research.

Wnt/β‑catenin signaling is critical for neurogenesis and neural progenitor fate determination,¹⁵⁷ and it also directly drives myelin gene expression and myelin formation.^158,159 Hyperglycemia and metabolic disturbances can disrupt this pathway. In vitro studies show that high glucose injures Schwann cells by inhibiting Wnt/β‑catenin signaling.¹⁶⁰ Compared with controls, Schwann cells exposed to high glucose show reduced proliferation, lower β‑catenin mRNA and protein levels, and increased GSK‑3β mRNA expression.¹⁶⁰ In STZ‑induced DPN rats, Wnt/β‑catenin signaling is also suppressed.¹⁶¹ In the sciatic nerve, β‑catenin expression decreases, while the Wnt antagonist WIF‑1 increases.¹⁶¹ The traditional preparation Jinmaitong improves diabetic neuropathy by activating Wnt/β‑catenin signaling, enhancing myelin protein zero (MPZ) secretion, and restoring MPZ levels.¹⁶¹ By contrast, some reports suggest that Wnt/β‑catenin may be overactivated at specific stages of diabetic neuropathy. In STZ‑induced DPN rats, Wnt pathway proteins increase in the lumbar spinal cord (L4–L6), dorsal root ganglia, and sciatic nerves. This activation is associated with heightened inflammation, ER stress, and reduced intraepidermal nerve fiber density (IENFD), leading to neurobehavioral deficits and impaired nerve function.¹³ Intrathecal delivery of a Wnt inhibitor lowered Wnt pathway proteins, reduced the inflammatory marker MMP2 and the ER stress marker GRP78, improved IENFD, and alleviated pain behaviors (thermal, cold, and mechanical hyperalgesia). It also improved nerve conduction velocity and nerve blood flow.¹³ These findings suggest that inhibiting Wnt signaling may have neuroprotective effects in DPN.

Overall, Wnt/β‑catenin signaling is closely linked to the development and progression of diabetic neuropathy and represents a potential therapeutic target.

Wnt/β‑Catenin Signaling and Diabetic Osteoporosis

Diabetic osteoporosis (DOP) is a major skeletal complication of diabetes, defined by loss of bone mass and disruption of bone microarchitecture. Osteoporosis has been reported in up to 60% of diabetic patients, and fracture risk is significantly increased in this group.^162,163 Although the exact mechanisms behind diabetes‑related bone loss remain unclear, accumulating evidence links hyperglycemia‑induced bone abnormalities to dysregulation of Wnt/β‑catenin signaling.^12,164

Wnt/β‑catenin signaling is essential for bone remodeling, maintaining the balance between osteoblast‑driven formation and osteoclast‑mediated resorption. When this pathway is disrupted, normal remodeling is impaired and osteoporosis develops.¹⁶⁵ Under physiological conditions, bone formation and resorption are tightly coupled. In diabetes, elevated ROS and AGEs suppress Wnt/β‑catenin activity¹⁶⁶ by reducing Wnt ligands and receptors such as LRP5,^167,168 while increasing endogenous inhibitors including DKK‑1, SOST and WIF‑1.^167–171 These alterations inhibit osteoblastogenesis, promote osteoclastogenesis and adipogenesis, and ultimately reduce bone formation while accelerating resorption.¹⁶⁷

Experimental studies support this mechanism. Shao et al reported markedly lower levels of Wnt1, Wnt3a, Wnt10b, and β‑catenin in STZ‑induced type 2 diabetic mice with osteoporosis.¹⁶⁷ Wang et al observed reduced LRP5 and osteoprotegerin expression at fracture sites in type 1 diabetic rats; blocking DKK‑1 and improving islet function enhanced bone remodeling.¹⁶⁸ Clinically, patients with T2DM and femoral fractures show elevated serum SOST,¹⁶⁹ suggesting that hyperglycemia may upregulate SOST and suppress canonical Wnt signaling, shifting bone turnover toward resorption and adipogenesis. In STZ‑induced T1DM mice, DKK‑1 is increased and β‑catenin reduced in the proximal tibia,¹⁷⁰ and WIF‑1 expression is higher in individuals with T2DM.¹⁷¹

Given its central role, Wnt/β‑catenin signaling has become a promising therapeutic target for DOP. In high‑glucose conditions, metformin activates this pathway in MC3T3‑E1 cells, promotes proliferation and mineralization, increases ALP activity, and upregulates osteogenic markers such as Runx2 and osteocalcin, thereby enhancing osteogenic differentiation.¹¹ Overall, Wnt/β‑catenin signaling provides a key molecular link between the diabetic environment and bone loss. A better understanding of its regulatory network may support the development of more effective strategies to prevent and treat DOP.

Therapeutic Agents Targeting Wnt/β‑Catenin Signaling in Diabetic Complications

The Wnt/β-catenin pathway has been increasingly recognized as a promising therapeutic target in diabetic complications, and considerable effort has been devoted to the development of agents that regulate this pathway. A number of inhibitors, including natural or engineered proteins, monoclonal antibodies, and small-molecule compounds, have been identified. Most of these agents act by antagonizing Wnt ligands, blocking receptor-mediated signaling, or inhibiting β-catenin activation. Some have already shown protective effects in experimental models of diabetic complications. Selected Wnt/β-catenin inhibitors and their effects are summarized in Table 1.

Table 1.

Therapeutic Drugs or Molecules Targeting the Wnt/β-Catenin Signaling Pathway for Diabetic Complications

Diabetic Complications	Inhibitor	Inhibition of Targets	Outcomes	Ref.
DN	Klotho-derived peptide 6 (KP6)	Binding directly to Wnt ligands	Reversing established proteinuria, attenuating glomerular hypertrophy, mitigating podocyte damage, and ameliorating glomerulosclerosis and interstitial fibrotic lesions	[172]
DR	Mab2F1	Anti-LRP6 antibody	Attenuating leukostasis, reducing vascular leakage, andx` diminishing inflammation in the retina of DR	[110]
	H1L1	Anti-LRP6 antibody
	SZN-413	FZD4 agonist (WNT mimetics)	Improving retinal non-perfusion and reducing vascular leakage	[173]
	Fenofibrate	Inhibiting oxidative stress-mediated Wnt/β-catenin pathway	Ameliorating diabetes-induced retinal vascular leakage and ameliorating DR	[97]
DCM	1.25-Dihydroxyvitamin-D3	Inhibiting the β-catenin/TCF4/GSK-3β/mTOR pathway	Attenuating the myocardial hypertrophy and interstitial fibrosis, improving cardiac function and restoring the impaired cardiac autophagy	[10]
DPN	LGK974 (porcupine inhibitor)	Inhibiting Wnt secretion without decreasing its synthesis	Showing improvement in pain-associated behaviors (heat, cold, and mechanical hyperalgesia) and nerve functions (motor, sensory nerve conduction velocities, and nerve blood flow) of DPN	[13]
	NSC668036 (disheveled inhibitor)	Binding to the Dvl-PDZ domain and blocks the PDZ-mediated interactions of Dvl
	PNU74654 (β-catenin inhibitor)	Destabilizing β-catenin and preventing its interaction with the TCF/LEF transcription factors
DOP	WAY-316606 (SFRP1 inhibitor)	Inhibiting SFRP1 from directly binding to Wnt or its receptor	Inhibiting osteoclastogenesis and promoting osteogenesis	[174]
	Metformin	Activating Wnt/β-catenin signaling pathway	Stimulating the proliferation and osteogenic differentiation of MC3T3-E1 cells	[11]

Traditional Chinese medicine (TCM) has also received growing attention in recent years for its potential role in the management of diabetic complications. Owing to its multi-component and multi-target nature, TCM may intervene in several pathological processes simultaneously. Recent studies have shown that TCM has therapeutic potential in a range of chronic metabolic, inflammatory, and fibrotic diseases. In kidney disorders in particular, including chronic kidney disease (CKD) and renal fibrosis, TCM formulations,¹⁷⁵ single-herb extracts,¹⁷⁶ and bioactive monomers^177,178 have been reported to reduce renal injury and slow fibrotic progression through multiple mechanisms, such as suppressing inflammation and oxidative stress, limiting extracellular matrix deposition, inhibiting epithelial–mesenchymal transition, and regulating profibrotic signaling networks.

Current evidence suggests that the therapeutic effects of TCM on diabetic complications are closely associated with modulation of the Wnt/β-catenin signaling pathway, although the direction of regulation appears to vary with the disease context. Among compound formulas, Tang-Shen-Ning¹⁷⁹ was reported to inhibit Wnt/β-catenin signaling in DN, thereby alleviating podocyte EMT and podocyte injury. Tangshen Formula¹⁴⁶ also suppressed this pathway and attenuated myocardial fibrosis in DCM. In contrast, some formulas appear to exert therapeutic effects through pathway activation under specific conditions. For instance, Ruyi Jinhuang Powder¹²⁴ promoted fibroblast proliferation and migration, accelerated wound healing, and reduced inflammation in DCU, while Liuwei Dihuang Pills¹⁸⁰ enhanced osteogenic differentiation in DOP. These findings indicate that the effects of compound formulas on Wnt/β-catenin signaling are dependent on the pathological setting. Studies on single-herb extracts and herb-derived fractions have mainly focused on DN. Salvia miltiorrhiza⁴⁵ improved renal injury and corrected abnormal glycolipid metabolism through inhibition of Wnt/β-catenin signaling. Mulberry leaf alkaloids and flavonoids extract¹⁸¹ alleviated metabolic disturbances and renal damage by inhibiting both Wnt/β-catenin and TGF-β/Smad signaling. Similarly, the ethyl acetate fraction EA-3 of Sang-Bai-Pi¹⁸² attenuated renal fibrosis through suppression of these two pathways. Panax notoginseng¹⁸³ was also shown to inhibit Wnt/β-catenin signaling and ameliorate albuminuria and podocyte EMT in diabetic rats. Overall, these studies suggest that herb-derived preparations may exert renoprotective effects largely through antifibrotic and metabolic mechanisms. Monomeric compounds have generally provided clearer mechanistic evidence. In DN, oridonin¹⁸⁴ inhibited Wnt/β-catenin signaling and alleviated renal fibrosis, whereas tanshinone IIA¹⁸⁵ regulated the VDR/Wnt/β-catenin axis and improved tubulointerstitial fibrosis. In DR, melatonin¹⁴ suppressed Wnt/β-catenin signaling and alleviated high glucose-induced retinal barrier disruption and angiogenic responses. In DCU, asiaticoside nitric oxide gel¹²³ and cycloastragenol¹⁸⁶ activated Wnt/β-catenin signaling and promoted wound repair. In DPN, Jinmaitong¹⁶¹ activated this pathway and improved neuropathic injury, whereas isoquercitrin¹⁸⁷ inhibited it and ameliorated pain-related and functional abnormalities. In DOP, morroniside¹⁸⁸ activated Wnt/β-catenin signaling and promoted osteoblast proliferation, differentiation, and mineralization. Taken together, these findings support an important role for Wnt/β-catenin signaling in the treatment of diabetic complications by TCM. However, its regulation is not uniform. In disorders characterized primarily by fibrosis and tissue injury, such as DN, DR, and DCM, inhibition of Wnt/β-catenin signaling appears to be more common, whereas in conditions involving tissue repair or differentiation, such as DCU and DOP, pathway activation may be beneficial. Representative TCMs targeting Wnt/β-catenin signaling in diabetic complications are summarized in Table 2.

Table 2.

TCMs Targeting the Wnt/β-Catenin Signaling Pathway for Diabetic Complications

Diabetic Complications	TCMs	Mechanism	Outcomes	Ref.
DN	Salvia miltiorrhiza	Inhibiting wnt/β-catenin signaling pathway	Improving the renal injury and regulation of abnormal glycolipid metabolism	[45]
	Mulberry leaf alkaloids and flavonoids extract	Inhibiting Wnt/β-catenin and TGF-β/Smads signaling pathway,	Relieving metabolic disorders and alleviating DN	[181]
	Sang-Bai-Pi fractions EA-3	Inhibiting TGF-β/Smad and Wnt/β-cate nin signaling pathways	Alleviating renal fibrosis	[182]
	Panax notoginseng	Inhibiting Wnt/β-catenin signaling pathway	Ameliorating albuminuria and podocyte EMT in diabetic rats	[183]
	Oridonin	Inhibiting Wnt/β-catenin signaling pathway	Alleviating fibrosis in DN	[184]
	Tang-Shen-Ning	Inhibiting Wnt/β-catenin signaling pathway	Ameliorating podocyte EMT and protecting podocytes from injury in DN	[179]
	Tanshinone IIA	Regulating VDR/Wnt/β-catenin pathway	Ameliorating tubulointerstitial fibrosis in rats with DN.	[185]
DR	Melatonin	Inhibiting Wnt/β-catenin pathway	Ameliorating HG-induced iBRB disruption, cell proliferation, cell migration, invasion and tube formation, and decreasing the expression levels of VEGF, MMP-2, and MMP-9	[14]
DCU	Ruyi Jinhuang Powder	Activating Wnt/β-catenin signaling pathway.	Promoting fibroblasts proliferation and migration, and accelerating unhealing wound and reducing wound inflammation	[124]
	Asiaticoside nitric oxide gel	Activating Wnt/β-catenin signaling pathway	Alleviating the inflammatory reaction of wound, increasing the expression of VEGF, iNOS, eNOS and CD34, and promoting DCU wound healing	[123]
	Cycloastragenol	Activating Wnt/β-catenin signaling pathway	Promoting the proliferation and migration ability of EpSCs, and increasing the expression levels of TERT, β-catenin, c-Myc.	[186]
DCM	Tangshen Formula	Inhibiting Wnt/β-catenin Pathways	Attenuating myocardial fibrosis in KKAy mice	[146]
DPN	Jinmaitong	Activating Wnt/β-catenin signaling pathway	Alleviating mechanical allodynia, ameliorating peripheral nerve morphological degeneration and diabetic-induced peripheral neuropathy	[161]
	Isoquercitrin	Inhibiting Wnt/β-catenin Pathways	Ameliorating the alterations in behavioral pain thresholds and improving functional parameters	[187]
DOP	Liuwei Dihuang Pills	Upregulating the Wnt/β-catenin signaling pathway	Elevating the expression of osteogenic differentiation proteins, including collagen I and RUNX2, and to increase the ALP activity in MC3T3-E1 cells for the treatment of OP	[180]
	Morroniside	Activating Wnt/β-catenin signaling pathway	Promoting osteoblast proliferation, differentiation, and mineralization.	[188]

Conclusion and Perspective

Wnt/β-catenin signaling has an important but highly context-dependent role in diabetic complications. Evidence from the kidney, retina, skin, heart, peripheral nervous system, and bone indicates that this pathway is involved in multiple diabetes-related processes, including oxidative stress, inflammation, fibrosis, abnormal angiogenesis, metabolic imbalance, and impaired tissue repair. Its effects, however, are not uniform. In some tissues, reduced signaling appears to impair homeostasis and regeneration, whereas in others, persistent activation aggravates structural injury and functional deterioration.

This context specificity is particularly evident across different complications. In diabetic nephropathy and neuropathy, both loss and overactivation of Wnt/β-catenin signaling have been linked to disease progression, suggesting that balanced pathway activity is critical. In diabetic retinopathy and cardiovascular complications, sustained activation seems more consistently associated with oxidative injury, inflammation, neovascularization, hypertrophy, and fibrosis. By contrast, in diabetic cutaneous ulcers and osteoporosis, insufficient pathway activity is more often associated with defective healing, impaired osteogenesis, and loss of tissue integrity.

The complexity of Wnt/β-catenin signaling is further shaped by its interaction with other pathogenic pathways, including TGF-β/Smad, NF-κB, renin-angiotensin, oxidative stress, and endoplasmic reticulum stress signaling. Future work should therefore focus on defining its cell-specific and stage-specific actions in diabetic tissues. Such efforts will be essential for determining whether therapeutic benefit lies in pathway inhibition, restoration, or selective modulation, and for translating mechanistic insight into more precise treatment strategies.

Funding Statement

This work was supported by the Clinical Research Fund for Hospital Pharmacy Optimization and Development of Shandong Pharmacists Association [PRP/SDLPA2101-2025].

Data Sharing Statement

This article does not report original data. No new data were created or analyzed in this study; therefore, data sharing is not applicable to this article.

Author Contributions

Xuelian Liu; Conceptualization, Formal Analysis, Writing – original draft. Yuefen Liu; Formal Analysis, Visualization, Writing – original draft. Yun Zhang; Conceptualization, Writing – review and editing, Supervision. Zhanqi Cao; Formal Analysis, Writing – review and editing. Qie Guo; Investigation, Writing – review and editing, Supervision. Hongyan Ji; Investigation, Project administration, Writing – review and editing. Donghua Liu; Conceptualization, Supervision, Writing – review and editing, Project administration. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors confirm that they have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication.