The canonical pathways involved in AJ assembly demonstrated the E-cadherin clustering controlled by the intracellular tail and the coupled actin cytoskeleton (Yap et al., 1998; Wu et al., 2015; Biswas and Zaidel-Bar, 2017). Specifically, the C-terminus of the intracellular tail interacts with a group of adaptor proteins called armadillo catenins, namely β-catenin and plakoglobin (γ-catenin), which anchor E-cadherin to the peri-junctional actin cytoskeleton. γ-Catenin is primarily localized at desmosomes and AJs, interacting with desmogleins/desmocollins and cadherins, respectively, and can compensate for β-catenin loss at AJs without disrupting desmosomal integrity (Diane Wickline et al., 2013). The E-cadherin-catenin complex -known as CCC- is composed of β-catenin (or plakoglobin), which directly tethers via its central Armadillo domain to the cytosolic tail of E-cadherin and via the N-terminal domain to α-catenin, which in turn links the compound to the actin filaments (F-actin) (Pećina-Šlaus, 2003; Kobielak and Fuchs, 2004; Hulpiau and Van Roy, 2009). The binding of α-catenin to F-actin requires α-catenin homodimers, whereas α-catenin binds to E-cadherin/β-catenin complex in its monomeric form. EPLIN (i.e., epithelial protein lost in neoplasm) represents the missing link between the CCC and the apical circumferential actin belt, coupling cortical actin filament bundles to the monomeric α-catenin of the assembly (Abe and Takeichi, 2008).

A highly conserved sequence in the juxtamembrane domain of E-cadherin is responsible for coupling with another catenin, named p120 catenin (p120ctn), whose binding is fundamental for the AJ assembly (Thoreson et al., 2000; Van Roy and Berx, 2008). p120ctn acts as a master regulator of E-cadherin’s cell surface delivery and functional integrity by inhibiting internalization pathways that promote E-cadherin degradation and facilitating plasma membrane recycling (Davis et al., 2003). It has been reported that the juxtamembrane region primarily mediates the lateral clustering of cadherin molecules, further reinforcing the role of p120ctn as a key contributor to cluster formation and adhesion strengthening (Yap et al., 1998). Moreover, p120ctn is an important mediator for the Rho-associated protein kinase (ROCK)/E-cadherin interaction. ROCK is a serine-threonine kinase involved in the regulation of cadherin function. Constitutive activation of ROCK leads to disruption of AJs, whereas pharmacological inhibition of ROCK promotes AJ stability (Wójciak-Stothard et al., 2001; Grothaus et al., 2018).

Post-translational processing of E-cadherin, most prominently including phosphorylation, O-glycosylation, N-glycosylation, and proteolytic cleavage, has been extensively described to dictate its function and redistribution dynamics. Serine phosphorylation of the β-catenin-binding domain, for instance, has been reported to be constitutive to cadherin-catenin complex formation and stabilization by increasing β-catenin binding affinity and regulating E-cadherin’s biosynthesis and trafficking (McEwen et al., 2014). Effector phosphorylation of p120ctn and β-catenin also seem to -inversely- contribute to the E-cadherin/catenin association and partly control E-cadherin’s surface stability (Roura et al., 1999; Fukumoto et al., 2008). Cytoplasmic O-glycosylation (O-GlcNAc) of newly synthesized E-cadherin regulates its secretory path, causing retention in the endoplasmic reticulum and cell surface transit arrest. In its absence, unimpeded export to the membrane delays apoptosis and rescues E-cadherin recruitment to adhesion sites (Geng et al., 2012). Ectodomain N-glycosylation constitutes the most prevalent post-translational modification, boasting four potential sites (two in EC4 and two in EC5) in the extracellular domain of human E-cadherin. In addition to E-cadherin folding and trafficking, N-glycan remodeling can be instrumental to functional junction organization, with the extent of N-glycan branching/complexity negatively associating with adhesive strength (Pinho et al., 2011). Another functionally-impairing post-translational event E-cadherin can undergo is proteolytic truncation by endogenous proteases, which more prominently results in the release of soluble E-cadherin (sE-cad) fragments, as discussed in more detail below. sE-cad is approximately 80 kDa in size, generated by α-secretase cleavage on the extracellular face of the plasma membrane, which is catalyzed by various proteases, including matrix metalloproteinases (MMPs), members of a disintegrin and metalloproteinase (ADAMs) family, plasmin, and kallikrein 7 (David and Rajasekaran, 2012). The shed sE-cad fragment can diffuse into the extracellular environment, where it retains the ability to form homophilic bonds and pair with intact, full-length molecules, interfering with the function of adhesion-competent E-cadherin. Moreover, it can chemotactically anchor E-cadherin on migrating cells and upregulate MMPs, thereby further destabilizing epithelial integrity (Samuels et al., 2023). Ectodomain shedding disrupts the intact E-cadherin junctional complexes, with circulating sE-cad harboring biological effect amplification in the context of proliferative and survival/apoptotic resistance signals, migratory and invasive abilities due to loss of barrier function, inflammation, and tumorigenesis (Grabowska, 2012). The remaining membrane-bound C-terminal fragment of E-cadherin (38 kDa, E-cad/CTF1) can then be cleaved by a γ-secretase/presenilin-1/2, injecting a 33-kDa E-cad/CTF2 fragment into the cytosol. This unleashes β-catenin which can promote the oncogenic canonical Wnt pathway, with E-cadherin sheddase matrilysin (MMP-7) among the transcriptional targets. Also, p120ctn remains E-cadherin-bound and can mediate E-cad/CTF2 translocation to the nucleus and subsequent DNA binding, where E-cad/CTF2 modulates p120ctn-Kaiso-mediated pathway to suppress apoptosis (Ferber et al., 2008). In addition to fragmentation into CTF1 and CTF2, generation of a 29kDa E-cad/CTF3 by caspase-3 has been observed in apoptosis and cancer progression (Craig and Brady-Kalnay, 2011; Yang et al., 2017).

Tungal et al. demonstrated that E-cadherin is crucial for maintaining epithelial barrier function in vivo by regulating TJ formation and stability. Specifically, E-cadherin coordinates the trafficking and positioning of TJ proteins, facilitating the localized integration of key molecules such as the cytoplasmic scaffolding zonula occludens 1 (ZO-1) and claudins, a family of integral membrane proteins that form TJs (Tunggal et al., 2005; Maiers et al., 2013). The communication between AJs, mediated by E-cadherin, and TJs plays a vital role in establishing inter-junctional co-dependence and directing the initial architecture of the epithelial barrier (Ando-Akatsuka et al., 1999; Lázaro et al., 2002; Tunggal et al., 2005).

The functional coupling of AJs and TJs is essential for the maturation of AJs and the early development of TJs. Early studies found that ZO-1 mobilization to the plasma membrane is mediated by catenins, enabling ZO-1 to co-distribute in areas segregated by E-cadherin (Rajasekaran et al., 1996). ZO-1, a key marker of TJs, is closely associated with AJs and the cadherin-catenin complex, transiently binding with α-catenin in nascent junctions (Maiers et al., 2013; Campbell et al., 2017). Knockdown of E-cadherin using siRNA has been shown to reduce ZO-1 expression and lower epithelial resistance in bronchial epithelial cells (Heijink et al., 2010). Additionally, loss of E-cadherin disrupts the organization of ZO-1 and F-actin, as E-cadherin-dependent mechanical circuits play a role in integrating force transduction and signaling pathways that drive junctional polarization necessary for functional epithelial barrier formation (Rübsam et al., 2017).

E-cadherin also regulates epidermal growth factor receptor (EGFR) activity and junctional tension to inhibit premature TJ complex formation in lower layers, while promoting TJ stability and cortical stiffness in apical layers. In E-cadherin knockout models, occludin—a transmembrane protein essential for TJs—and its cytosolic connector ZO-1 exhibit a more punctate or discontinuous pattern at cellular interfaces, explaining why TJ barrier function is compromised in the absence of E-cadherin (Rübsam et al., 2017).

Moreover, TJ proteins can influence E-cadherin regulation. For instance, introducing mutated ZO-1 into a ZO-null cell line inhibits the maturation of AJs during epithelial polarization (Ikenouchi et al., 2007). Additionally, overexpression of claudin-1 has been shown to drive the transcriptional downregulation of E-cadherin through the transcriptional repressor ZEB-1 (Singh et al., 2011). In contrast, overexpression of claudin-7 upregulates E-cadherin expression and enhances cell-cell adhesion, whereas E-cadherin expression does not appear to induce an increase in claudin-7 (Lioni et al., 2007).

The Wnt signaling pathways are evolutionarily conserved cellular communication networks that play a key role in both normal physiological and disease states. Several studies have reported that Wnt signaling governs processes such as cell fate determination, differentiation, proliferation, migration, and polarity. The pathway is divided into two main branches: the canonical Wnt/β-catenin pathway, which involves the stabilization and nuclear translocation of β-catenin, and the non-canonical Wnt pathways, such as the planar cell polarity (PCP) pathway, which operate independently of β-catenin (Komiya and Habas, 2008; Katoh, 2017; Flores-Hernández et al., 2020). Of note, E-cadherin/β-catenin membranous interaction and colocalization sequesters β-catenin to the membrane, inhibiting Wnt activation and epithelial-to-mesenchymal transition (EMT) by averting nuclear translocation of β-catenin. The Wnt/β-catenin signaling culminates in the nucleus with the formation of the TCF/LEF complex, initiating the transcription of Wnt target genes. Loss of E-cadherin results in downregulation of membrane β-catenin binding, whereas nuclear mutant β-catenin induces EMT, dysregulating the assembly of TJs and AJs (Kim et al., 2019). Also, E-cadherin/β-catenin interaction maintains low levels of cytoplasmic β-catenin fraction by inhibiting Wnt signaling (Stockinger et al., 2001). In reverse, the absence of Wnt stimulus empowers β-catenin phosphorylation by a destruction complex consisting of APC, Axin, GSK3β, and CK1, which marks β-catenin for degradation by the proteasome (Stamos and Weis, 2013). β-catenin´s growth-inducing transcriptional activity can thus be counteracted by E-cadherin, which in turn induces cell cycle arrest or, more pronouncedly, apoptosis (Stockinger et al., 2001).

The Hippo pathway is another evolutionarily conserved signaling network that regulates cell-cell communication and tissue homeostasis across species. It integrates environmental signals, including cellular polarity, contact inhibition, soluble factors, and mechanical stimuli, to regulate key biological processes such as cell proliferation, organ/tissue size, development, and regeneration (Cheng et al., 2020; Ahmad et al., 2022; Fu et al., 2022; Nita and Moroishi, 2024; Zhong et al., 2024). It primarily regulates the phosphorylation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) by LATS1/2 kinases at multiple serine residues. This phosphorylation facilitates the binding of 14-3-3 proteins, resulting in the retention of YAP/TAZ in the cytoplasm, preventing their nuclear translocation and transcriptional activity, and potentially leading to their proteolytic degradation in the cytosol (Cheng et al., 2020; Zhong et al., 2024). Upon LATS1/2 inactivation, unphosphorylated YAP/TAZ translocate to the nucleus, where it functions as a transcriptional co-activator by associating with the transcriptional enhanced associate domain (TEAD) transcription factor family (Kaan et al., 2017; He et al., 2021). The resulting YAP/TAZ-TEAD complex facilitates the transcriptional activation of numerous target genes, including those encoding critical junctional proteins such as desmogleins and E-cadherin. Inhibition of YAP–TEAD interactions lead to a substantial decrease in both YAP and phospho-YAP levels, significantly impairing cell–cell junction integrity and resulting in the disassembly of AJs and desmosomes (Ahmad et al., 2022). Kim et al. demonstrated that cell-cell adhesion, mediated by homophilic binding of E-cadherin, contributes to YAP inactivation (Kim et al., 2011). Perturbing the E-cadherin/α-catenin complex reduces YAP phosphorylation and increases YAP nuclear accumulation and activity (Kim et al., 2011; Lamar et al., 2012). Studies have shown that the regulation of Hippo pathway kinases and the sequestration of YAP occur at AJs, where several Hippo pathway components are localized (Pan et al., 2018; Ma et al., 2020; Ahmad et al., 2022).

Several studies have also established a connection between Hippo signaling and cell-cell contact through the regulation of TJs, including ZO proteins (Kaan et al., 2017; Ahmad et al., 2022; Guo et al., 2022). Specifically, AMOTL2, a member of the Angiomotin (AMOT) family of proteins, binds directly to the WW domains of YAP via its PPxY motifs, sequestering YAP at TJs and preventing its nuclear activity. In addition, it has been shown that AMOTL2 interacts with LATS2, permitting the recruitment of upstream Hippo components, such as SAV1, to the junctional complex. The interaction between AMOTL2 and LATS2 also facilitates LATS2-mediated YAP phosphorylation, cytoplasmic retention, and inactivation (Paramasivam et al., 2011; Zhao et al., 2011). Intriguingly, the scaffolding functions of AMOTL2 have been described beyond YAP and LATS2, including multiple other junctional proteins like ZO-1 and β-catenin, thus contributing to maintenance of TJ integrity and epithelial polarity (Zhao et al., 2011; Kim et al., 2021). Hippo and canonical Wnt have been reported to engage in crosstalk, particularly through the YAP effector; YAP/TAZ has been described as part of the β-catenin destruction complex and can modulate the Wnt/β-catenin response and β-catenin degradation; in Wnt-OFF cells, YAP/TAZ cytoplasmic sequestration as part of the destruction complex, inhibits Wnt/β-catenin signaling in the cytoplasm. Conversely, in nucleus, YAP/TAZ can contribute to β-catenin-mediated transactivation of genes, with the two co-activators complexing and β-catenin/YAP/TAZ/TEAD co-regulating target genes. Finally, YAP can be a Wnt/β-catenin target gene, with its expression being a driver of proliferation in cancer cells (Konsavage and Yochum, 2013; Sileo et al., 2022).

E-cadherin cleavage to an 80 kDa soluble fragment is one of the primary mechanisms known to provoke functional loss of E-cadherin. The cleavage of E-cadherin is more commonly attributed to matrix metalloproteinases, including MMP-3 (stromelysin-1), MMP-7 (matrilysin), MMP-9 (gelatinase B or gelatinase type IV), as well as certain ADAMs such as ADAM10 (adamalysin) (Noë et al., 2001; David and Rajasekaran, 2012; Boukhedouni et al., 2020; Tao et al., 2021; Im et al., 2022).

In addition to bacterial stimulation of the host’s native sheddases, proteases encoded and secreted by pathogens have also been described to catalyze E-cadherin fragmentation, independent of endogenous enzymes.

Bacterial pathogens can seemingly affect E-cadherin expression on a transcriptional level as well as subvert epigenetic alterations that lead to junctional disturbances. P. gingivalis-lipopolysaccharide (LPS) substantially reduced E-cadherin protein expression in epi-4 cells compared to no P. gingivalis-LPS challenge (Abe-Yutori et al., 2017). This expression pattern has been demonstrated in chronic periodontitis subjects, showing a statistically significant decrease in E-cadherin levels compared to healthy individuals, which inversely correlated with K19 increase (Nagarakanti et al., 2007). Semiquantitative immunohistochemical analysis of tissue samples detected a statistically significant reduction in staining intensity from the external oral epithelium, through the gingival sulcus, to the junctional epithelium of clinically healthy gingiva, with the most marked decrease seen in the pathological lining of the pocket epithelium (Ye et al., 2000). In murine gingivitis epithelia, noticeably decreased E-cadherin expression was observed under the inflamed condition on a protein and mRNA level. This was inversely associated with induction of pyroptosis, namely programmed cell death triggered by caspase-1 activation, where caspase-1 and E-cadherin were inversely correlated (Li et al., 2021).

Clostridium perfringens beta2 (CPB2) toxin was shown to confer intestinal epithelial barrier injury in porcine IPEC-J2 cells treated with 20 μg/mL rCPB2 by considerably restricting claudin-1 and E-cadherin mRNA and protein expression levels (Gao et al., 2020). In a transcriptomic analysis of human trophoblast cells (BeWo), many junctional protein genes were recognized as differentially expressed in response to E. faecalis infection, including E-cadherin, which was found significantly downregulated (Tan et al., 2018). E-cadherin transcripts were measured to be progressively inactivated over time in Shigella dysenteriae-infected HT29 cells, with ensuing β-catenin cytoplasmic translocation (Raja et al., 2012).

CDH1 promoter hypermethylation of CpG islands is one of the most common epigenetic patterns that transcriptionally suppress E-cadherin expression. This epigenetic modification is widely considered to have a greater frequency in H. pylori chronic gastritis and constitutes an established early event in gastric carcinogenesis (Chan, 2003; Kang et al., 2003; Liu et al., 2005). In a study, methylation density in gastric body and antral mucosae obtained from H. pylori-positive gastritis patients was approximately 10-fold higher compared to H. pylori-negative patients. The study showed that host inflammatory cytokines and growth factors -including TNF-α, MG132 (ROS), and EGF in response to the infection mediate aberrant E-cadherin methylation and DNA methyltransferase (DNMT) activity in vitro (Miyazaki et al., 2007). IL-1β-stimulated NF-κB cascade activation and DNMT induction via NO production is another compelling transcriptional system engaged in H. pylori-associated hypermethylation status, which conceivably links chronic gastric inflammation and carcinogenesis (Huang et al., 2012). Successful H. pylori eradication therapy notably eliminates methylation effects and results in reversal of prior silencing (Chan, 2006; Leung et al., 2006; Miyazaki et al., 2007), potentially reinstating E-cadherin expression-dependent barrier function. Interestingly, the opportunistic pathogen Acinetobacter baumannii was also found capable of hindering E-cadherin expression through promoter CpG methylation following its nuclear trafficking (Moon et al., 2012). In the pathophysiological course of Chlamydia trachomatis infection, EMT induction also seems to entail methylation increment in the E-cadherin promoter, while upregulation of other mesenchymal markers was not proven to stem from significant epigenetic alterations (Rajić et al., 2017).

Given that the extracellular part of E-cadherin engages in homotypic and heterotypic interactions to achieve cell aggregation and control cell behavior, bacteria can seize the molecule’s ectodomain as a heterophilic receptor for adherence and uptake by host cells. L. monocytogenes, a food-borne pathogen able of prototypic intracytosolic invasion in non-phagocytic cells, can employ a well-described invasion protein named internalin (lnlA) to interact with the N-terminal EC1 domain via a leucine-rich repeat (LRR) of the bacterial ligand, securing attachment and internalization at the site of the bacterial-epithelial interface (Mengaud et al., 1996; Schubert et al., 2002). Upon specific calcium-requiring anchoring to E-cadherin, L. monocytogenes can initiate lnlA-based and locally constrained entry into the epithelial cells at the sites of bacterial contact without inducing dramatic morphological changes. This type of bacterial ligand-promoted endocytosis more closely resembles the “zipper mechanism” of Yersinia entry but is distinct from Salmonella “trigger” invasion mechanism (Mengaud et al., 1996). Bonazzi et al. showed that lnlA attachment induces sequential E-cadherin post-translational modifications, which are prerequisites for the recruitment of the different components of endocytosis machinery at the bacterial entry site. In this regard, induced Src-mediated phosphorylation and ubiquitination by ubiquitin-ligase Hakai at the juxtamembrane E-cadherin domain were required for caveolin-dependent E-cadherin clustering and clathrin-mediated internalization (Bonazzi et al., 2008). In fetoplacental listeriosis, L. monocytogenes crosses the maternofetal or trophoblastic barrier via heterotypic interaction between accessible syncytiotrophoblast E-cadherin with lnlA, as recapitulated ex vivo in human placental extracts (Lecuit et al., 2004). In the intestinal villi, where E-cadherin is naturally basolateral and secluded from the lumen, L. monocytogenes was shown to exploit transient defects of epithelial polarity and junctional remodeling spots to facilitate penetration. Indeed, multicellular junctions formation in cell extrusion zones of villus tip can function as entry points and enable the pathogen to efficiently reach the apically exposed E-cadherin prior to its dynamin-dependent removal from the cell surface (Pentecost et al., 2010). Apart from extruding apoptotic cells on villi tips or cells located within intestinal epithelial folds, reorganization of apical junctional complexes around goblet cells, which is affected by physical tensions associated with mucus-expelling dynamics, can similarly make E-cadherin luminally accessible. This allows lnlA-initiated rapid transcytosis across intestinal villi vertical axis with ultimate bacterial release from the basal pole of enterocytes into the lamina propria (Nikitas et al., 2011). Of note, even though InlA binding to E-cadherin is indispensable and adequate for Listeria attachment, modulation by another internalin (InlB) expedites invasion through the displaced junctions and synergistically promotes endocytosis through activation of c-Met signaling (Pentecost et al., 2010). Ultimately, the strength of lnlA-E-cadherin interaction per se may not directly correlate with the invasive capacity, conceivably reflecting lnlA’s non-exclusive role in determining L. monocytogenes virulence (Dellafiora et al., 2020). Intriguingly, invasion can also involve other host cell-dependent mechanisms such as cell membrane perforation to hijack the endocytic machinery by use of pore-forming exotoxin listeriolysin O; extracellular Ca²⁺ influx and Rac1 activation-dependent downstream signaling lead to actin cytoskeleton de novo assembly mandated for Listeria’s internalization (Lam et al., 2018).

Pneumococcal surface adhesin A (PsaA) of Streptococcus pneumoniae has been identified as another heterophilic ligand of E-cadherin during the initial stage of bacterial colonization in the nasopharyngeal (NP) epithelium. PsaA binding was found to be calcium-dependent and, unlike lnlA that is specific to human E-cadherin, both human and mouse E-cadherin were able to inhibit adherence of PsaA-coated fluospheres to NP cells (Anderton et al., 2007).

Login et al. demonstrated that EPEC microcolonies also recruit E-cadherin at intercellular junctions of polarized and nonpolarized cells. However, only after the initial establishment of interaction between bacterial intimin and the Tir receptor on the host membrane, is E-cadherin able to bind to the Tir-intimin complex. Nonetheless, E-cadherin still influences EPEC attachment as the absence of the extracellular domain of E-cadherin significantly reduced EPEC adhesiveness (Login et al., 2018).

Another adhesin, FadA, was described to bind to the EC5 domain of E-cadherin, promoting attachment and invasion in colorectal cancer (CRC) and non-CRC cells under Fusobacterium nucleatum infection. In CRC cells, interaction of E-cadherin with FadA was shown to induce downstream β-catenin signaling. Specifically, E-cadherin phosphorylation, internalization of the complex, cytoplasmic translocation of β-catenin, and transcriptional activation of Wnt/β-catenin target genes were shown to be induced (Rubinstein et al., 2013). F. nucleatum may thus promote the malignant phenotype of CRC by enhancing tumor growth, inflammatory responses, and EMT through interaction with E-cadherin. However, F. nucleatum only increased the inflammatory responses when β-catenin expression was knocked down in normal colonic cells, whereas no changes were observed when E-cadherin expression was knocked down (Ma et al., 2018).

Bacterial toxins have also been shown to associate with the E-cadherin receptor, disrupting the intercellular epithelial continuity to allow their subsequent uptake. Hemagglutinin (HA) constitutes a nontoxic accessory component of the botulinum neurotoxin complex, produced by Clostridium botulinum and known to cause flaccid paralysis in animals and humans. HA was found to bind to E-cadherin on EC1-EC2 residues in a species-specific manner, disrupting its function by sterically blocking E-cadherin trans-dimerization (Sugawara et al., 2010; Lee et al., 2014).

H. pylori virulence factor CagA can also interact physically with E-cadherin, functionally impairing E-cadherin/β-catenin complex assembly in gastric epithelial cells independently of CagA tyrosine phosphorylation status. The resultant β-catenin cytosolic and nuclear accumulation can transactivate β-catenin-regulated signaling, including intestinal-specific transdifferentiation genes, implicated in metaplasia and gastric carcinogenesis (Murata-Kamiya et al., 2007). Oliveira and colleagues later suggested that CagA interacts with E-cadherin and p120ctn in a c-Met-dependent manner, promoting multiprotein formation between CagA, c-Met, E-cadherin, and p120ctn. This interestingly inhibits c-Met and p120ctn phosphorylation and restrains the invasive phenotype induced by H. pylori (Oliveira et al., 2009).

Interestingly, E-cadherin was found to serve as an adherence receptor for C. difficile spores onto intestinal epithelial cells (IECs). Castro-Córdova et al. observed that E-cadherin was able to bind to the hairlike projections of the spores, and that the E-cadherin-specific interaction with IECs was toxin-mediated, requiring TcdA and TcdB to open the AJs and render E-cadherin accessible for tethering (Castro-Córdova et al., 2023).

Cadherins have been previously described as able receptors for Leptospira (Evangelista et al., 2014). Pereira et al. identified E-cadherin as a binding receptor for protein Lsa16 of L. interrogans (Pereira et al., 2017). Kochi and co-workers reported that two putative leptospiral surface-exposed lipoproteins LIC11711 and LIC12587, conserved among pathogenic strains of L. interrogans, show binding affinity to E-cadherin in a dose-dependent interaction that allows initial bacterial attachment to host epithelial cells (Kochi et al., 2019). Potential host cell membrane injury and E-cadherin expression changes following leptospirotic attachment have been previously described. Cell membrane insult as the primary cellular lesion of leptospirosis was corroborated immunohistochemically, with E-cadherin expression irregularities in leptospirotic patients and loss of membrane E-cadherin in hepatocytes, associated with liver-plate disarray (De Brito et al., 2006). Strikingly, this E-cadherin downregulation might be attributed to feedback inhibition mechanisms that eventually decrease Leptospira colonization. It has been described that LRR proteins expressed by the pathogenic Leptospira species can interact with E-cadherin on the host cell surface, inducing E-cadherin/β-catenin and NF-κB signaling cross-talk that can ultimately dictate the fate of E-cadherin and regulate Leptospira adhesion and invasion in kidney (Hsu et al., 2021).

A range of lung diseases, including idiopathic pulmonary fibrosis, COPD, and asthma have been associated with loss of E-cadherin function and elevated sE-cad levels (Yuksel et al., 2021; Mottais et al., 2023). Although E-cadherin loss and/or proteolytic processing are observed in inflammatory conditions, it remains unclear whether these changes are a primary cause of disease pathophysiology or simply a secondary response.

In vitro and in vivo lung injury studies have demonstrated that MMP-7 mediates the cleavage of extracellular E-cadherin, promoting epithelial repair and facilitating cell migration through the redistribution of E-cadherin-based adhesions in wounded epithelium (McGuire et al., 2003). Interestingly, E-cadherin interaction with the αEβ7-integrin receptor or CD103, both of which are expressed on pulmonary anti-fibrotic DCs, is regulated by MMP-7. This interaction promotes the resolution of acute neutrophilic inflammation and induces an anti-inflammatory cytokine profile, thereby balancing epithelial repair with immune activation (Manicone et al., 2009). Interestingly, sE-cad levels were significantly elevated in the BAL fluids and serum of mice with bleomycin-induced pulmonary fibrosis. sE-cad promotes EMT in the alveolar epithelium and abnormal fibroblast migration. Blocking sE-cad effectively reduced myofibroblast accumulation and collagen deposition in the lungs following bleomycin exposure. Additionally, transforming growth factor-β1 (TGF-β1) was found to stimulate the shedding of sE-cad from A549 cells and promote EMT, with these effects being reversed upon sE-cad inhibition (Huang et al., 2024).

Studies by Ghosh et al. have shown loss of E-cadherin in the lung epithelium of patients with COPD. Ghosh et al. reported that knockout of E-cadherin in alveolar epithelial type II but not type I cells in adult mouse models results in airspace enlargement. Furthermore, the knockout of E-cadherin in airway ciliated cells, but not club cells, increases airway hyperreactivity (Ghosh et al., 2022). Additionally, cigarette smoke-induced epithelial injury has previously been linked to E-cadherin-related barrier dysfunction (Nishida et al., 2017; Ghosh et al., 2020). As anticipated, significantly higher levels of sE-cad were found in the plasma of COPD patients and symptomatic smokers compared to healthy smokers and nonsmokers. Moreover, both plasma and epithelial lining fluid (ELF) sE-cad levels were positively correlated with the severity of airway limitation, with ELF sE-cad levels showing a particularly strong correlation with MMP-7 levels (Shirahata et al., 2018).

In the context of asthma development, common environmental factors such as air pollutants are known to impair the airway epithelial barrier by reducing E-cadherin expression. Exposure to sub-toxic levels of soluble PM2.5, diesel exhaust, and other reactive oxygen species (ROS)-generating pollutants has been shown to decrease E-cadherin levels. This reduction in E-cadherin contributes to airway barrier dysfunction, which can increase susceptibility to bacterial infections. The silencing of the E-cadherin gene due to air pollutants may be mediated by dysregulated non-coding RNAs, which are overexpressed in asthma and COPD patients (Aghapour et al., 2022). A study by Michaudel et al. demonstrated that ozone-induced respiratory barrier injury—characterized by protein leak, epithelial cell desquamation, and the recruitment of neutrophils and alveolar macrophages—precedes myeloid cell-driven lung inflammation, bypassing the protective effects of the IL-33/ST2 axis. Acute ozone exposure disrupts IL-33-dependent homeostasis, leading to decreased epithelial E-cadherin expression and increased inflammatory cell infiltration in the absence of ST2 and IL-33. Additionally, the deposition of air pollutants leads to E-cadherin depletion via an HMGB1-mediated mechanism, contributing to abnormal alveolar cell turnover in emphysema (Michaudel et al., 2018). Also it has been reported that loss of E-cadherin upon pollutant exposure triggers cell senescence, chronic disruption of alveolar differentiation, and apoptosis through downstream effectors of the Hippo pathway, such as YAP/TAZ (Chang et al., 2022). Furthermore, recent studies have also linked the upregulation of FcϵRI, monomeric IgE, and IgE/FcϵRI engagement with decreased junctional distribution of E-cadherin in severe asthma. The crosstalk between FcϵRI and EGFR was found to be associated with E-cadherin loss, triggering IL-33 synthesis and release upon IgE-induced EGFR activation (Weng et al., 2023). Heijink and colleagues observed that EGFR phosphorylation and activation following E-cadherin silencing drives EGFR-dependent recruitment of Th2 cells in allergic asthma, through the induction of TARC/CCL2, a Th2-attracting molecule (Heijink et al., 2007). Another mechanism by which environmental factors disrupt the epithelial barrier involves proteolytically active allergens that cleave E-cadherin, either directly through proteolytic activity or indirectly by triggering pattern-recognition receptors (PRRs). Protease allergens activate innate immune receptors such as protease-activated receptors (PARs) and stimulate non-IgE-mediated reactions, leading to the release of mediators (Yuksel et al., 2021). For example, mite allergens induce proteolysis of ZO-1, occludin, and other TJ proteins, while proteases released by pollen disrupt E-cadherin and TJ proteins like occludin and claudin-1. Moreover, proteases found in mite, fungi, and cockroach extracts activate PAR1/2, which subsequently leads to the degradation of E-cadherin (Yuksel et al., 2021). Finally, higher sE-cad levels are associated with more severe asthma, correlating with sputum HMGB1 level and glucocorticoid dosage required for daily management. In addition to that, sputum sE-cad levels reflect asthma severity and inversely correlate with decreases in FEV1 (Masuyama et al., 2003). Upon allergen exposure, significant increases in sE-cad levels were observed in the BAL fluids of mice. It is believed that sE-cad contributes to airway inflammation in severe asthma through ERK signaling, which upregulates VEGF and IL-6, and promotes the infiltration of neutrophils and eosinophils into the airways (Tang et al., 2024).

Gingivitis and periodontitis are oral diseases characterized by dysbiosis, periodontium destruction, and aberrant immune responses of the host. In chronic inflammatory conditions, (i.e., periodontitis), E-cadherin expression in epithelium is significantly downregulated during pocket formation (Nagarakanti et al., 2007; Saliem et al., 2023). Notably, elevated sE-cad salivary levels were shown to positively correlate with periodontitis severity (Kazem et al., 2023). Notably, gingival crevicular fluid (GCF) E-cadherin significantly increased in gingivitis and periodontitis cases as compared to controls (Hussein et al., 2024b). E-cadherin levels in GCF has been shown to be a good predictor for nonsurgical periodontal therapy outcomes in periodontitis patients (Hussein et al., 2024a).

Several mechanisms are involved in the regulation of E-cadherin in periodontitis. Specifically, a study by Hiyoshi et al. has shown that NE disrupts the gingival epithelial barrier by degrading E-cadherin, allowing periodontal pathogens to penetrate the periodontal tissues (Hiyoshi et al., 2022). Also, in the pathological epithelial lining of periodontal pockets, the reduction of E-cadherin has been linked to the EMT phenotype (Saliem et al., 2022, 2023; Kadeh et al., 2023). In an epigenetic study, hypermethylation of CpG islands in the CDH1 gene was detected in 25% of patients with chronic periodontitis, whereas no such hypermethylation was observed in healthy individuals (Loo et al., 2010). In this context, epigenetic silencing has been previously shown to contribute to the inactivation of E-cadherin (Strathdee, 2002). Finally, physiological mechanical stress (e.g., mastication, interstitial pressure, and dental manipulations) compromised E-cadherin intracellular levels and translocation (Lee et al., 2023; Vitkov et al., 2023).

E-cadherin plays a crucial role in maintaining intestinal epithelial function and regulating the inflammatory immune response. Disruption of E-cadherin-mediated cell-cell adhesion has been linked to increased intestinal permeability, commonly referred to as “leaky gut,” as well as enhanced infiltration of inflammatory cells—two key pathophysiological features of IBD. E-cadherin deficiency is associated with more pronounced colitis and histopathological changes related to tissue repair, as well as increased disease severity (Grill et al., 2015). Reduced E-cadherin expression correlates with the duration and severity of symptoms in IBD patients (Wilcz-Villega et al., 2014). In mucosal samples from patients with chronic active UC, decreased E-cadherin was primarily observed at the lateral membranes of enterocytes, particularly near sites of active PMN transmigration (Kucharzik et al., 2001). Furthermore, Motta et al. (2021) identified elastase 2A (ELA2A), an epithelium-derived elastase distinct from leukocyte-secreted NE, and linked epithelial elastolytic overload in colonic cells of IBD patients to E-cadherin degradation. ELA2A hyperactivity was associated with a pro-inflammatory phenotype, leading to dysregulation of the cytokine profile (e.g., upregulation of IL-8/CXCL8, a neutrophil chemoattractant) and activation of intestinal mucosal immunity (Motta et al., 2021). In addition to the “autocrine” regulation of downstream signaling processes caused by the post-shedding E-cadherin disarrangement, a “paracrine” loop involving the released soluble fragments has also been hinted (Hu et al., 2016). Intriguingly, E-cadherin peptide fragments themselves -found in chronic inflammatory states such as IBD- possess biological properties that contribute to mucosal wound healing (Gordon et al., 2019).

Exacerbated mucosal injury in adulthood may result from neonatal stressor exposure and associated epigenetic changes. Specific CDH1 polymorphisms, such as the CDH1 GTC risk haplotype (a 3-SNP haplotype: rs12597188, rs10431923, and rs9935563), which has an estimated allelic frequency of 21%, have been linked to abnormal E-cadherin trafficking and are significantly associated with an increased susceptibility to Crohn’s disease (Muise et al., 2009). Elevated miRNA expression is a hallmark of inflammation and EMT in IBD and is inversely correlated with CDH1 expression in inflamed mucosa (Guz et al., 2020). In a “dual insult” model of neonatal and adult colonic inflammation, TNF-α-regulated epigenetic activation of miRNA-155 (miR-155) was found to significantly suppress E-cadherin expression for a prolonged period, compared to both single insult and control groups (Kline et al., 2020). A study by Tian has shown that upregulation of miR-155 inhibits post-transcriptional E-cadherin protein synthesis through a RhoA-dependent mechanism (Tian, 2013). Also, miR-21a-5p has been shown to be upregulated in exosomes derived from intraperitoneal macrophages in a DSS-induced enteritis model. A negative correlation was observed between exosomal miR-21a-5p and E-cadherin expression in enterocytes (Lu et al., 2021).

The adhesive properties of E-cadherin on immune cells, such as DCs, are also implicated in colitis development. Ihara et al. (2018) found that E-cadherin was upregulated in a tissue-resident subset of lamina propria CD11c+ DCs in CD11c-Cre TGF-βr2fl/fl mice. E-cadherin-mediated interactions between CD11c+ monocytes and the intestinal epithelium promoted Notch signaling activation. When combined with the abrogated inhibitory effects of TGF-β, this interaction was colitogenic, driving dysbiosis and abnormal epithelial differentiation (Ihara et al., 2018). Additionally, the homing of E-cadherin+CD11+ monocyte-derived DCs to mesenteric lymph nodes in colitic mice may play a key role in T-cell-mediated gut inflammation, with TGF-β appearing to limit this effect (Siddiqui et al., 2010). These DCs can activate naïve T-cells through robust cytokine and chemokine secretion. Adoptive transfer of these cells to immunodeficient hosts led to the expansion of the E-cadherin+ DC population at sites of accumulation and promoted Th17 responses. Notably, this subset exhibited high MHC II expression, along with significantly elevated levels of toll-like receptors and CCR2, compared to E-cadherin (-) DCs, highlighting their heightened sensitivity to microbial triggers and increased inflammatory potential (Siddiqui et al., 2010). Furthermore, E-cadherin was found to engage in inhibitory interactions with KLRG1 on group 2 innate lymphoid cells (ILC2). Upon E-cadherin depletion, this interaction is disrupted, resulting in increased Th2 cytokine levels and excessive ILC2 induction (Lu et al., 2021).

Finally, epithelial barrier dysfunction via E-cadherin proteolysis has been increasingly implicated in the pathogenesis of gastroesophageal reflux disease (GERD) (Jovov et al., 2011; Samuels et al., 2023; Lu et al., 2024). The presence of a 35-kDa intracellular C-terminal fragment and an increase in soluble N-terminal fragments of E-cadherin in sera of GERD patients have been previously reported. This is attributed to ADAM10-mediated cleavage of E-cadherin, which leads to enhanced esophageal epithelial permeability (Jovov et al., 2011). Also, pepsin-pH4 has been shown to cause E-cadherin fragmentation, which is not salvaged by known E-cadherin sheddase inhibitors. Acidified pepsin can cleave full-length E-cadherin (125 kDa), resulting in 38 and 33 kDa C-terminal E-cad/CTF1 and E-cad/CTF2 fragments, respectively, indicative of regulated intramembrane proteolysis (RIP). Furthermore, it can induce ADAM10 maturation and drive transcriptional targets of E-cadherin RIP fragments such as MMPs (Samuels et al., 2023). Aside from GERD, E-cadherin downregulation has also been reported in the pathogenesis of laryngopharyngeal reflux disease (LPRD), with increased levels of MMP-7-mediated degradation being observed in LPRD biopsies (Reichel et al., 2008; Im et al., 2022).

Spontaneous preterm birth (PTB) and preterm pre-labor rupture of the membranes (pPROM) are major pregnancy complications where E-cadherin alterations have been implicated as part of the EMT process (López-Novoa and Nieto, 2009; Sisto et al., 2021; Menon, 2022). Interestingly, preterm labor is triggered by EMT-associated inflammation and immune imbalances at the fetomaternal interface (Menon et al., 2020). Human amnion cells can undergo non-canonical EMT, including the downregulation of E-cadherin, in response to inflammatory mediators such as TNF-α. This process predisposes the fetal membranes to weakening, increasing the risk of preterm birth (De Castro Silva et al., 2020).

Pre-eclampsia (PE) is also a common pregnancy complication involving an inflammatory phenotype and immune perturbations at the fetoplacental unit (Cornelius, 2018; Michalczyk et al., 2020). E-cadherin shedding, regulation, and transport play crucial roles in trophoblast differentiation, fusion, and physiological placental formation (Shih et al., 2002; Aghababaei et al., 2015; Iwahashi et al., 2018). However, preeclamptic extravillous trophoblasts showed a decrease in their E-cadherin expression indicating the significance of E-cadherin in trophoblast function (Blechschmidt et al., 2007). Mechanistic studies in early-onset PE placental tissues showed that E-cadherin expression is associated with the downregulation of ribosomal protein L39 and the loss of its suppressive control (Jie et al., 2021). Circular RNAs and miRNAs have also been implicated in modulating E-cadherin expression, contributing to the molecular events underlying PE pathogenesis (Zhu et al., 2020).

Although E-cadherin expression typically declines during progressing gestation, in pregnancies complicated by PE, placental E-cadherin levels significantly increase at the protein level. This may reflect abnormal cytotrophoblast proliferation relative to syncytiotrophoblasts, indicating an imbalance in the trophoblastic proliferative unit (Brown et al., 2005). This aligns with a study by Benian et al., which displayed that elevated E-cadherin levels, as well as IL-10 and TGF-β1, were significantly higher, were significantly higher in plasma and placentae of PE patients (Benian, 2002). Immunohistochemical discontinuity of E-cadherin expression in the syncytiotrophoblastic basal membrane can constitute a marker of impaired placental barrier integrity, and by extension pregnancy-induced hypertension or PE (Pęksa et al., 2022). Despite that, E-cadherin upregulation in the syncytiotrophoblast of preeclamptic placentae has not been considered a disease severity marker (Li et al., 2014).

In placenta accreta and percreta, trophoblastic E-cadherin is significantly reduced (Duzyj et al., 2015; Incebiyik et al., 2016). Similarly, the reduction in E-cadherin expression of placental villi has been reported in gestational trophoblastic diseases (Li et al., 2003; Xue et al., 2003). Loss of E-cadherin, induced by Snail upregulation under hypoxic conditions, can activate α5-integrin signaling and promote extravillous trophoblast invasiveness (Arimoto-Ishida et al., 2009).

E-cadherin plays an important role in pancreatitis and autodigestive inflammatory diseases. Specifically, cathepsin C (CTSC) has been reported as an activator of NE, which degrades E-cadherin. Notably, in models with CTSC deletion, E-cadherin cleavage—though not neutrophil motility—was reduced, resulting in milder disease (John et al., 2019). Importantly, E-cadherin breakdown can be entirely mediated by NE, without the need for the proteolytic activity of native pancreatic enzymes (Mayerle et al., 2005).

In atopic dermatitis, E-cadherin has been identified as a proteolytic substrate of granzyme B, a serine protease that, along with perforin, is known to mediate lymphocyte-induced apoptosis (Turner et al., 2021). This suggests that E-cadherin functions as a “double-faced” molecule, playing roles in both adhesion and signaling. Its degradation, particularly during neutrophil transmigration mediated by NE, not only causes epithelial injury but also promotes the proliferation of surviving epithelial cells to facilitate repair or potentially drive pathological remodeling. The shedding of E-cadherin’s ectodomain ultimately supports re-epithelialization by promoting β-catenin signaling and its translocation to the nucleus, potentially upregulating canonical Wnt signaling to mitigate collateral epithelial damage (Zemans et al., 2011).

Several proteolytic cascades are involved in E-cadherin degradation and the disassembly of AJs, including a variety of enzymes such as zinc-dependent MMPs, ADAMs, cathepsins, kallikrein-7, plasmin, and calpain, all of which catalyze the proteolytic cleavage of E-cadherin (Rios-Doria et al., 2003; Grabowska, 2012). In eczematous dermatitis, soluble stimuli like LPS, proinflammatory cytokines, and TGF-β significantly increase ADAM10-dependent E-cadherin shedding, impairing keratinocyte cohesion and contributing to the disease’s molecular pathology through the activation of MAPK signaling, which regulates sE-cad release (Maretzky et al., 2008). Of note, enhanced metalloprotease-catalyzed production of sE-cad has also been linked to EGFR activation (Zuo et al., 2011). Furthermore, ADAM15-mediated ectodomain shedding plays a role in stabilizing HER2 and HER3 heterodimerization, leading to receptor activation and proliferative signaling (Najy et al., 2008).

In renal tissue damage and inflammation, E-cadherin is found to be down-regulated upon cisplatin-induced acute renal injury (AKI), whereas E-cadherin levels amelioration is suggested to alleviate the inflammatory effects and rescue from AKI (Gao et al., 2018). E-cadherin overexpression in M2 macrophages (IL-4/IL-13-induced, alternatively activated macrophages) has been shown to attenuate the inflammatory cytokine response to LPS stimulation, indicating a protective, anti-inflammatory role of E-cadherin on immune cells (Van Den Bossche et al., 2015). Conversely, a pro-inflammatory capacity of sE-cad has been identified, contributing to TNF-α production in synovitis via its interaction with lectin receptor LRG1 on T-cells (Lode Melis et al., 2014).

In prostate tissue, intact membrane E-cadherin has been found to be considerably downregulated with age and inflammation (Pascal et al., 2021). In fact, one of the hallmarks of benign prostate hyperplasia, termed “inflammaging” (i.e., chronic slow-progressing inflammation in the aging prostate), was phenotypically enhanced even in E-cadherin deficient mice without complete deletion (CDH1^+/- mice), accompanied by increased prostatic macrophage infiltration and bladder overactivity (Pascal et al., 2022).

In posterior capsular opacification, a complication of cataract surgery, proliferation, migration, and EMT/fibrotic characters of residual lens epithelial cells are observed. IL-8 seems to promote EMT by mediating CXCR1/2/NF-κB/p65 signal and subsequent RhoA activation, suppressing the expression of E-cadherin and ZO-1 to facilitate cell migration (Si et al., 2024). Downregulation of junctional proteins, including E-cadherin, claudins and occludin has been reported in other scar epithelia, including idiopathic subglottic stenosis (Berges et al., 2024).

Interestingly, supplemental vitamin D was recently reported to reinforce E-cadherin-based junctions by suppressing TNF-α-induced NF-κB signaling and consequently downregulating degradative MMP-9 production in vitro (Oh et al., 2019). Vitamin D can regress LPS-triggered inflammation in oral keratinocytes by hindering NF-κB activation (Zhao et al., 2018). Vitamin D in its 1.25(OH)₂D₃ form is also known to regulate EMT and activity of TGF-β and Wnt/β-catenin signaling pathways, in addition to controlling E-cadherin turnover through modulating expression profiles of effectors on E-cadherin degradation and membranal stabilization, like p120ctn, Kaiso, and NEDD9 (Sari et al., 2020). Promisingly, vitamin D treatment exerts its protective effects in vivo by rescuing E-cadherin expression and enhancing binding affinity and membranal sequestration of β-catenin in conjunction with attenuating transcriptional activity and nuclear fraction of the latter (Xin et al., 2017). MART-10, a noncalcemic calcitriol analogue, significantly inhibited MMP-2 and MMP-9 synthesis more potently compared to 1α,25(OH)₂D₃, while it blocked the EMT process by bolstering E-cadherin expression and downregulating suppressive transcription factors Snail and Slug (Chiang et al., 2014).

10-Hydroxy-cis-12-octadecenoic acid (HYA), a bioactive product of fatty acid metabolism in probiotic microorganisms such as Lactobacillus spp., has previously exhibited barrier-recovering effects. In DSS-colitis mice, orally administered HYA restored TJ molecules and alleviated intestinal inflammation through G protein-coupled receptor 40 (GPR40) (Miyamoto et al., 2015). In experimental periodontitis, activation of GPR40 by HYA ameliorated gingival barrier function and repressed local inflammatory cytokine production in vivo. Notably, HYA was found to endow E-cadherin with proteolytic resistance against P. gingivalis, suggestively through post-translational modifications conferred in a HYA-GPR40-ERK-dependent manner (Yamada et al., 2018).

Gut symbionts are well-known to display anti-inflammatory properties, with Akkermansia muciniphila being a representative Gram(-) anaerobe. In calvarial infection and experimental periodontitis, A. muciniphila attenuated P. gingivalis-induced bone destruction and inflammatory responses; the gut symbiont suppressed pro-inflammatory IL-12 secretion and gingipain generation, whereas it raised anti-inflammatory IL-10, and improved the expression of junctional markers integrin-β1, E-cadherin and ZO-1 (Huck et al., 2020). Lactobacillus gasseri ATCC33323 supplementation was shown to protect the intestinal mucosal barrier and alleviate colitic lesions in mice, by ameliorating inflammatory cell infiltration and inflammatory markers (IL-1β, IL-6, TNFα). Importantly, it led to recovery of junctional proteins like E-cadherin, ZO-1, claudin-1, and occludin, retaining the localization of E-cadherin/β-catenin and E-cadherin/p120ctn complexes. Specifically, it promoted E-cadherin expression via regulation of CDH1 transcription by NR1I3, which potentially contributed to the anti-inflammatory effects (Qian et al., 2024).

Inhibition of E-cadherin-degrading proteases such as MMPs and bacterial proteases is a principal approach to abrogate the destabilizing effects of E-cadherin cleavage. The group of Haderer and others used broad-spectrum MMP inhibitor batimastat (BB-94) as a blocker of E-cadherin degradation in Caco-2 and live SBP-inducing bacteria (E. coli and P. mirabilis) co-culture setup (Haderer et al., 2022). Of note, batimastat was one of the first MMP inhibitors to be used in clinical trials, particularly in malignant ascites (Parsons et al., 1997). Yet, it remains classified as an experimental drug as it did not progress to widespread clinical use in humans, paving the way for the development of other MMP inhibitors with improved pharmacological properties.

Inhibitor GI254023X, a hydroxamate-based inhibitor preferentially blocking ADAM10, was found to abrogate E-cadherin shedding in a dose-dependent manner, retaining E-cadherin cell surface expression and preventing β-catenin translocation after ionomycin treatment in HaCaT keratinocytes (Maretzky et al., 2005).

More recently, amprenavir, an identified HIV protease inhibitor, has shown some promise in antireflux chemopreventive potential, rescuing the esophageal epithelial barrier from acidified pepsin-mediated barrier disruption, and protecting against E-cadherin cleavage, and MMP induction. In this study using BAR-T cells, 10 µM amprenavir fully salvaged pepsin-mediated cell dissociation and notably rescued E-cadherin RIP, with increased full-length E-cadherin and decreased 33 and 38 kDa fragments compared to acidified pepsin alone. 1 µM amprenavir only partially protected from pepsin-induced dissociation and yielded a slight increase of full-length E-cadherin. Also, 10 μM amprenavir led to statistically significant inhibition of pH4 pepsin-mediated upregulation of MMPs -1, -7, -9, and -14 (Blaine-Sauer et al., 2023).

Bandyopadhyay et al. showed that activating E-cadherin monoclonal antibodies (mAbs) promoted epithelial barrier function in vitro and in vivo and hindered inflammatory progression in IBD (Bandyopadhyay et al., 2021). The human E-cadherin activating antibody Fabs selectively mitigated the loss of barrier function and reduced the decrease in TEER in epithelial cells exposed to inflammatory stimuli, such as RSV-L19 infection, in vitro. Additionally, it enhanced barrier function by increasing TEER in resting C2BBe1 Caco2 cells, where there was constitutive downregulation of junctional proteins. Treatment with E-cadherin activating mAbs significantly limited IBD progression in IL10-/- mice with spontaneous UC, as measured with histology, lesion severity scores, and non-invasive biomarkers fecal lipocalin 2 and albumin protein content in mice stool, implying a restoration of the barrier function (Bandyopadhyay et al., 2021).

Alternative approaches that prevent E-cadherin-mediated bacterial adhesion to epithelial cells have also been described. Banxia Xiexin Decoction, a clinically effective traditional Chinese treatment for colitis was founded to delay the colitis-to-cancer progression by inhibiting F. nucleatum colonization on colonic epithelial cells. This occurs by interfering with the binding of adhesin FadA to E-cadherin expressed on the colonic epithelium as well as dampening the activation of the E-cadherin/β-catenin downstream signaling, as observed by downregulation of targets β-catenin, Axin2, and Cyclin D1 (Jiang et al., 2024).

Polysaccharides chitin and more specifically, oral administration of its derivative chitosan (Q) was found to modulate the E-cadherin-αEβ7 (CD103) axis, involving TLR4 and IFNAR signaling to reinforce the intestinal barrier integrity. E-cadherin and αEβ7 interaction plays a critical role in anchoring intraepithelial lymphocytes to the epithelium, where they establish their intestinal barrier residence. Q was shown to enhance epithelial cell migration, wound healing and increase E-cadherin expression in IEC-18 cells in vitro and isolated IECs in vivo, priming CD103 induction in lymphocytes and promoting their localization on the epithelium. This process is thought to drive a stronger immunosurveillance and potentially protect against pathogens (Moine et al., 2024).

Lately, heat-killed non-viable probiotics have been explored as a potential strategy for mounting immune responses in infections and promoting barrier function in wound healing. Intriguingly, the use of non-viable heat-killed bacteria, such as tyndallized bacteria (TB) was shown to significantly enhance E-cadherin levels in bronchial cells. Moreover, TB exposure contributed to airway epithelium´s barrier function and repair potential, in conjunction with reduced release of TGF-β1, which could have a counteracting effect on EMT (Di Vincenzo et al., 2024).

Interestingly, ferroptosis inhibitors, such as ferrostatin-1, have been shown to alleviate alveolar epithelial damage by restoring E-cadherin. Ferroptosis, namely regulated death accompanied by iron accumulation and lipid peroxidation, has been associated with exposure to environmental pollutants and allergens and appears to inversely correlate with E-cadherin-mediated epithelial integrity. Strikingly, in ferroptosis models induced by birch pollen allergen Bet v, ferrostatin-1 treatment rescued E-cadherin levels both in vitro and in the lung of Bet v 1-challenged asthmatic mice (Ma et al., 2024).