Type VIII collagen is a member of the short-chain, non-fibrillar collagen family. It was first isolated in the 1980s by Helene Sage and colleagues from the culture medium of adult bovine aortic endothelial cells and was initially termed endothelial collagen (Sage et al., 1980). The protein is composed of two genetically distinct α chains, α1 (Col8a1) and α2 (Col8a2), each with an approximate molecular mass of 60 kDa (Loeffler et al., 2011). Subsequent studies demonstrated that type VIII collagen can assemble into discontinuous triple-helical molecules in cultured proliferating cells, with a major chain molecular weight of approximately 180 kDa (Kapoor et al., 1988). Type VIII collagen exhibits notable trimeric heterogeneity (Mann et al., 1990). In addition to the conventional α1/α2 heterotrimers, it can also form homotrimers composed exclusively of either α1 or α2 chains (Rosenblum, 1996; Greenhill et al., 2000), a feature that likely contributes to its functional diversity. Both Col8a1 and Col8a2 are expressed across multiple cell types (Sage et al., 1980; Paulus et al., 1991; Benya, 1980; Sage et al., 1983; Sage et al., 1984; Benya and Padilla, 1986; Rüger et al., 1994; Adiguzel et al., 2013). The full-length human Col8a1 and Col8a2 proteins consist of 744 and 704 amino acids, respectively (Ma et al., 2012). The Col8a1 gene is located on chromosome 3, whereas Col8a2 resides on chromosome 1. Structurally, each α chain contains a short collagenous triple-helix domain flanked by a C-terminal non-collagenous domain (NC1) and an N-terminal non-collagenous domain (NC2) (Muragaki et al., 1991). Structural information on type VIII collagen remains incomplete. Currently, only crystal structures of the NC1 domain are available in the Protein Data Bank (PDB: 1O91), whereas the full-length triple-helical structure has not been resolved, likely due to technical challenges associated with crystallizing flexible collagenous regions. Analysis of the trimeric crystal structure of the murine NC1 domain reveals that it belongs to the C1q-like protein family and forms a stable homotrimer. The surface of this domain contains bands enriched in aromatic residues that are thought to facilitate supramolecular assembly. Notably, unlike type X collagen, the NC1 domain of type VIII collagen lacks characteristic calcium-binding clusters, suggesting a distinct assembly mechanism (Kvansakul et al., 2003). Functionally, the NC1 domain is critical for trimer stabilization and contributes to basement membrane organization.

Type VIII collagen is widely distributed across human tissues. Early immunohistochemical investigations (Kittelberger et al., 1990) described it as “ubiquitously expressed with limited tissue specificity,” based on its detection in diverse basement membranes and connective tissues, including the descemet membrane of the corneal endothelium, sclera, choroid, optic nerve sheath, tendon, skin, periosteum, perichondrium, and glomerular mesangium (Altenbach et al., 1990; Franzke et al., 2003; Stephan et al., 2004; Sawada et al., 1990).

However, recent large-scale transcriptomic and proteomic analyses change this traditional view. Data from the Human Protein Atlas, which systematically classifies genes encoding extracellular matrix (ECM) and secreted proteins, demonstrate that most ECM-associated genes display tissue-enhanced or group-enriched expression profiles at the mRNA level, whereas only a small fraction exhibit truly ubiquitous expression. These findings indicate that ECM components, including collagens, show pronounced tissue specificity, suggesting that the in vivo distribution of type VIII collagen is likely more selective and regulated than previously appreciated (Naba et al., 2016).

Furthermore, evidence from the 29-tissue paired proteome–transcriptome atlas and the mass spectrometry (Naba, 2023) –based “extracellular matrix protein atlas” (McCabe et al., 2023) further supports the tissue-specific expression of collagen family members. These studies reveal marked organ-dependent variation in both expression abundance and subtype composition patterns. Such findings underscore that the tissue-selective expression of extracellular matrix components—particularly collagens—is a critical determinant of local matrix composition, structural organization, and mechanical properties.

Analyses of Col8a1/Col8a2 expression from the Human Protein Atlas (Wang et al., 2019), together with integrative studies of vascular disease–related datasets (Li et al., 2024) indicate that both transcripts and proteins are most abundantly expressed in the cornea, myocardium, large and medium-sized arteries, lung, and kidney. In contrast, expression remains low in parenchymal cell types such as hepatocytes and neurons, yielding an overall pattern of vascular and basement membrane–enriched expression with clear organ-specific biases. Notably, Col8a2 has been identified as a core structural component of the descemet membrane in the corneal endothelium, and its expression is markedly dysregulated in corneal disorders, including Fuchs’ endothelial corneal dystrophy.

In renal tissue, early studies reported that type VIII collagen is predominantly localized to the glomerular mesangium and segments of small vascular basement membranes. More recent investigation in aged mouse kidneys (Vo et al., 2024) has demonstrated a significant age-dependent increase in Col8a1 expression within the glomeruli, tubular basement membranes, and renal interstitium. This upregulation is closely associated with structural remodeling of the kidney, including interstitial fibrosis and microvascular rarefaction. Collectively, these findings indicate that type VIII collagen undergoes age-related regional enrichment in the kidney and may contribute to progressive renal remodeling.

From a cellular origin perspective, recent transcriptomic and single-cell RNA-sequencing studies demonstrate that type VIII collagen is not exclusively produced by vascular endothelial cells and vascular smooth muscle cells. Instead, it is also synthesized by organ-resident fibroblasts (Ford et al., 2023)、glomerular mesangial cells, adipose-derived stromal cells (Zhu et al., 2021), tumor-associated fibroblasts (Zhou X. et al., 2024), and other immune-related stromal populations. Notably, under pathological conditions such as inflammation, fibrosis, and tumor microenvironment remodeling, expression of type VIII collagen is further upregulated, highlighting its context-dependent regulation and functional relevance in disease states.

By integrating evidence from traditional immunohistochemical approaches with contemporary multi-omics analyses, this study demonstrates that although type VIII collagen is broadly distributed, it exhibits pronounced enrichment and functional specificity in selected tissues and cell types, particularly in the cornea, kidney, and systemic vasculature (Naba, 2023). Accordingly, type VIII collagen should not be regarded as a collagen subtype “lacking tissue specificity.” The in vivo distribution profile is summarized in Figure 1.

Type VIII collagen is a critical regulator of arterial injury repair and atherosclerotic progression. Gerth et al. (2007) demonstrated, using in vitro cell culture and matrix-coating assays, that COL8 is markedly upregulated during neointimal formation after vascular injury and during atherosclerotic plaque remodeling. In this context, COL8 mediates smooth muscle cell (SMC) adhesion and chemotaxis via integrin-dependent mechanisms and enhances matrix metalloproteinase (MMP) expression, thereby promoting SMC migration and invasion. Complementary findings by Liu et al. (2024), using an in vitro fibrous cap model, further elucidated the role of COL8 in plaque stabilization. COL8 expression was significantly increased within the atherosclerotic microenvironment, particularly at stages critical for fibrous cap formation. Mechanistically, COL8 facilitated SMC migration and vascular wall remodeling through specific interactions with oxidized phospholipids.

Together, these studies define that COL8 contributes to the development of vascular disease.

Type VIII collagen is markedly upregulated during the progression of diabetic nephropathy. Li et al. (2024) reported significantly increased COL8 mRNA and protein levels in renal tissues from diabetic mouse models and in biopsy specimens from patients with diabetic nephropathy compared with controls. Aberrant accumulation of COL8 in the glomerular basement membrane is closely associated with disease progression, contributing to basement membrane thickening and glomerulosclerosis and thereby impairing renal filtration (Hopfer et al., 2009). Such structural alterations ultimately promote proteinuria, a hallmark clinical feature of diabetic nephropathy Collectively, these findings indicate that COL8 not only serves as a pathological biomarker but also actively participates in disease pathogenesis. Mechanistic insights provided by Loeffler et al. further implicate (Loeffler et al., 2011) COL8 in mesangial cell dysfunction.

Pharmacological inhibition studies revealed that COL8 modulates TGF-β1–induced mesangial cell proliferation in association with the PI3K/Akt signaling pathway. Blockade of PI3K/Akt partially reversed COL8-mediated effects on cell proliferation and related protein expression, suggesting that COL8 influences TGF-β1–driven responses through this pathway. Given the central role of TGF-β1 in promoting extracellular matrix accumulation and renal fibrosis, these data support COL8 as a promising molecular target for therapeutic intervention in diabetic nephropathy.

Type VIII collagen is increasingly recognized as a pro-fibrotic extracellular matrix (ECM) component with important roles in cardiovascular, renal, pulmonary, and ocular pathology (Skrbic et al., 2015). In the heart, COL8 contributes not only to matrix accumulation, but also to the maintenance of ventricular wall integrity during remodeling. Integrated single-cell RNA sequencing and spatial transcriptomic analyses have identified a distinct Col8a1 ⁺ fibroblast subpopulation as a central effector of tissue fibrosis. In injured and failing myocardium, this subset co-expresses WNT2 and WNT4 together with canonical pro-fibrotic mediators, including transforming growth factor-β (TGF-β), platelet-derived growth factors (PDGFs), and fibroblast growth factors (FGFs). Its activation is closely associated with aberrant NF-κB and Hippo–YAP signaling, which synergistically drive excessive collagen deposition and ECM stiffening (Ma et al., 2024).

Analogous Col8a1-overexpressing fibroblast or stromal cell clusters have been described in pulmonary and cutaneous fibrosis, where they co-express matrix-associated genes (e.g., COL1A1, COL3A1, LOXL2, and ELN) and localize to regions of increased tissue stiffness and myofibroblast enrichment (Redente et al., 2020). In the kidney, COL8 expression is elevated in experimental diabetic nephropathy and age-related fibrosis (Loeffler et al., 2012). In streptozotocin-induced models, COL8 accumulation in glomerular and tubular basement membranes correlates with epithelial dedifferentiation and epithelial–mesenchymal transition (EMT)–like changes, whereas genetic or pharmacological suppression attenuates mesangial expansion and interstitial fibrosis (Moss et al., 2022). In aged mouse kidneys, increased Col8a1/Col8a2 expression is associated with type I/III collagen deposition, microvascular rarefaction, and declining renal function, implicating COL8 in age-related ECM remodeling (Vo et al., 2024). Metabolic fragments of COL8 have also emerged as informative biomarkers of fibrotic activity. In conditions such as chronic obstructive pulmonary disease and liver fibrosis—where vascular remodeling and basement membrane turnover are prominent—circulating levels of the C-terminal COL8 fragment (C8-C) are markedly elevated, reflecting enhanced collagen degradation and tissue remodeling (Hansen et al., 2016). In ocular fibrosis, increased Col8a1 expression and deposition in Tenon’s capsule and conjunctiva correlate with postoperative scarring, further supporting a generalized role for COL8 in myofibroblast-rich fibrotic matrices (Seet et al., 2017).

In vivo evidence from Col8a1/Col8a2 knockout models demonstrates a dual function for COL8. While wild-type animals exhibit pronounced stress-induced fibrotic remodeling, COL8 deficiency confers protection against matrix accumulation but also leads to maladaptive phenotypes, including premature mortality, ventricular dilation, and cardiac dysfunction (Skrbic et al., 2015). These findings indicate that COL8 not only promotes fibrotic matrix formation but is also essential for preserving tissue integrity under mechanical stress. Consistent with observations in the cornea and kidney, loss of COL8 disrupts basement membrane architecture, underscoring its integral role as a mechanosensitive ECM component that links matrix remodeling to structural stability.

High-throughput transcriptomic profiling and pan-cancer analyses indicate that Col8a1 is among the most consistently upregulated network-forming collagens across a broad spectrum of solid tumors. Elevated Col8a1 expression is associated with advanced disease stage, extracellular matrix activation, and reduced overall survival in gastric, colorectal, breast, lung, renal, and pancreatic cancers (Zhou et al., 2020). Mechanistically, type VIII collagen facilitates tumor progression through both tumor cell–intrinsic mechanisms and tumor microenvironment–mediated pathways. In gliomas, Col8a1 is preferentially overexpressed in high-grade tumors and correlates with poor clinical outcomes. Functional studies further show that Col8a1 promotes glioma cell proliferation, migration, and invasion by activating FAK, AKT, and ERK signaling cascades, whereas Col8a1 knockdown suppresses tumor growth in vivo and reprograms the tumor microenvironment toward a less immunosuppressive state (Liu et al., 2024).

In papillary thyroid carcinoma and breast cancer, overexpression of Col8a1 promotes epithelial–mesenchymal transition (EMT), upregulates EMT-associated transcription factors and matrix metalloproteinases, and is associated with aggressive clinicopathological characteristics (Liang et al., 2024). In gastrointestinal malignancies, type VIII collagen is strongly linked to cancer-associated fibroblasts (CAFs) and the development of chemoresistance. In colorectal cancer, THBS2⁺ CAFs secrete Col8a1, which engages ITGB1 on tumor cells and activates the PI3K–AKT pathway, thereby inducing EMT and conferring resistance to oxaliplatin; pharmacological or genetic inhibition of ITGB1 or AKT reverses Col8a1-mediated drug resistance (Zhou X. et al., 2024). Pan-cancer collagen network analyses further identify Col8a1 as a central node in CAF-enriched, profibrotic tumors, where it co-localizes with other fibrotic collagens (e.g., COL1A1, COL3A1, and COL11A1) and TGF-β–responsive gene signatures (Le et al., 2020). In gastric cancer, multiple independent clinical and experimental studies show that Col8a1 is significantly upregulated in tumor tissues relative to normal gastric mucosa. High Col8a1 expression correlates with advanced disease stage, poor prognosis, EMT activation, increased angiogenesis, and chemoresistance. Functional assays demonstrate that Col8a1 silencing suppresses tumor cell proliferation, invasion, and metastatic potential, while enhancing sensitivity to cytotoxic agents in both in vitro models and in vivo xenografts, supporting its potential as a therapeutic target and a predictive biomarker for chemotherapy response (She et al., 2022). A similar paradigm is observed in pancreatic ductal adenocarcinoma (PDAC), where tumor- and stroma-derived Col8a1 establishes autocrine and paracrine loops that promote tumor cell survival and drug resistance; elevated Col8a1 expression is associated with poor prognosis in resected PDAC (Yan et al., 2022).

Collectively, these studies reveal convergent themes across multiple dimensions of cancer biology. First, type VIII collagen is markedly enriched within pro-fibrogenic, cancer-associated fibroblast (CAF)–dominated tumor microenvironments, where it cooperates with fibrillar collagens and other extracellular matrix (ECM) components to promote matrix stiffening and tumor invasion. Second, Col8a1 functions as a pro-tumorigenic ligand in cancer cells by activating integrin-dependent FAK–PI3K–AKT signaling and downstream epithelial–mesenchymal transition (EMT) and survival pathways. Third, type VIII collagen–derived fragments and circulating neoepitopes show promise as noninvasive biomarkers that reflect matrix activation, ECM remodeling, and therapeutic response. Together with its established involvement in fibrotic disorders, these findings position type VIII collagen as a critical molecular link between chronic fibrosis, profibrotic tumor microenvironments, and malignant progression.

Type VIII collagen is encoded by the Col8a1 and Col8a2 genes, which produce the α1(VIII) and α2(VIII) chains, respectively. Newly synthesized α1(VIII) and α2(VIII) polypeptides undergo extensive post-translational modifications before assembling into biologically functional type VIII collagen, with hydroxylation representing a critical regulatory step. Within the lumen of the rough endoplasmic reticulum, specific proline and lysine residues are hydroxylated by prolyl hydroxylase (Yamauchi and Sricholpech, 2012) and lysyl hydroxylase (Sricholpech et al., 2012) respectively, generating hydroxyproline and hydroxylysine. These reactions require Fe²⁺ and vitamin C as essential cofactors, with α-ketoglutarate serving as a co-substrate (Salo and Myllyharju, 2021). Hydroxylation, particularly of proline residues, markedly enhances the thermal stability of the collagen triple helix (Myllylä et al., 1988). Accordingly, vitamin C deficiency impairs hydroxylase activity, disrupts collagen biosynthesis, and results in scurvy, which is clinically characterized by vascular fragility and delayed wound healing (Needleman and Greenwald, 1986). In addition, pathogenic variants in Col8a2, such as L450W and Q455K, have been shown to impair hydroxylation, leading to endoplasmic reticulum retention of mutant proteins and failure of proper triple-helix assembly (Gottsch et al., 2005). Collectively, these findings underscore the essential role of hydroxylation in the intracellular processing, secretion, and biological function of type VIII collagen.

In addition to hydroxylation, type VIII collagen undergoes glycosylation, one of the most abundant and structurally diverse post-translational modifications in proteins (Hennet, 2019). This process involves sequential enzymatic reactions within the endoplasmic reticulum and Golgi apparatus mediated by multiple glycosyltransferases and glycosidases (Lowe and Marth, 2003; Schjoldager et al., 2020). In these compartments, galactosyltransferases and glucosyltransferases catalyze the attachment of glucose, galactose, and related disaccharides to 5-hydroxylysine residues (Schegg et al., 2009). Glycosylation of specific hydroxylysine sites within the triple-helical domain is essential for the structural integrity and functional activity of type VIII collagen (Yamauchi and Sricholpech, 2012). Mass spectrometry analyses indicate that corneal-derived Col8a2 is glycosylated at Hyl-450 and Hyl-455, whereas vascular-derived Col8a1 exhibits lower overall glycosylation, suggesting tissue-specific regulation (Basak et al., 2016). Although the precise functional consequences remain incompletely defined, available evidence indicates that glycosylation may influence collagen supramolecular organization, fiber orientation, and cell–matrix interactions (Torre-Blanco et al., 1992). Variation in glycan composition and site occupancy across tissues likely modulates protein stability, chain selection, and biological activity. Trimer assembly initiates at the C-terminal NC1 domain, which functions as the folding nucleus and determines trimer stoichiometry (Gansner and Gitlin, 2008). High-resolution structural studies further demonstrate that the NC1 domain adopts a C1q-like β-sandwich fold that mediates chain-specific recognition and stabilizes trimer formation (Kvansakul et al., 2003). Despite these insights, the complete in vivo trafficking route of type VIII collagen—from endoplasmic reticulum and Golgi processing through vesicular transport, secretion, and extracellular lattice assembly—has not been fully delineated and is largely inferred from other collagen types. Notably, genetic ablation of Col8a1 or Col8a2 in mice results in thinning and structural abnormalities of Descemet’s membrane, providing in vivo confirmation that proper intracellular trimer assembly is essential for basement membrane integrity (Stunf, 2022).

Unlike fibrillar collagens, type VIII collagen retains its N- and C-terminal non-collagenous domains after secretion, which are essential for supramolecular assembly (Karamanos et al., 2021). Ultrastructural analyses of human and bovine Descemet’s membranes by electron microscopy reveal highly ordered hexagonal lattices composed of type VIII collagen, characterized by repeating pillar-like structures approximately 160 nm in length that form a honeycomb-like, two-dimensional network (Sawada et al., 1990). Biochemical and recombinant protein studies further demonstrate that assembly follows a hierarchical process: secreted trimers first associate into basic oligomers through NC1 domain–mediated interactions, which then organize into higher-order tetrahedral complexes (Illidge et al., 2001).

α1(VIII) homotrimers assemble into tetrahedral units consisting of four trimers arranged symmetrically around a central NC1 core, a structure identified as the minimal supramolecular building block of the type VIII collagen network (Stephan et al., 2004). Through lateral associations and angle-specific interactions, these tetrahedra further organize into planar hexagonal lattice sheets, which subsequently stack and undergo cross-linking to form the dense and mechanically resilient three-dimensional architecture characteristic of Descemet’s membrane (Sawada et al., 1990). Thus, despite its relatively short collagenous domains, type VIII collagen constructs robust extracellular matrix structures through specialized oligomerization rather than classical fibril formation.

Type VIII collagen lattices co-localize with and integrate into basement membranes together with canonical components, including type IV collagen, laminins, nidogen, and heparan sulfate proteoglycans (Song et al., 2021). This integration confers biomechanical stability, regulates hydration and molecular diffusion, supports endothelial cell polarity and adhesion, and enhances resistance to deformation and mechanical stress (Ali et al., 2016; Saikia et al., 2018). Histological and ultrastructural analyses subdivide the postelastic layer of Descemet’s membrane into two regions: an anterior banded zone (ABZ) enriched in hexagonal type VIII collagen lattices, and a posterior non-banded zone (PNBZ) containing a mixed network of type VIII and type IV collagens, laminins, and proteoglycans (de Oliveira et al., 2020). Ongoing synthesis of type VIII collagen throughout adulthood contributes to age-associated thickening of the PNBZ (Jun et al., 2006).

Pathogenic variants in Col8a1 or Col8a2, particularly within the NC1 domain, disrupt trimerization and hexagonal lattice assembly, leading to compromised endothelial polarity, impaired barrier function, and altered ZO-1 distribution (Gottsch et al., 2005). These defects are central to early-onset Fuchs’ endothelial corneal dystrophy (FECD). In addition, oxidative stress, inflammation, and age-related declines in endothelial secretory capacity further impair type VIII collagen assembly, underscoring its critical role in maintaining basement membrane structure and function (Ong Tone et al., 2021).

Type VIII collagen has attracted increasing interest in regenerative medicine and tissue engineering because of its distinctive capacity to promote endothelial cell adhesion, migration, and microenvironmental organization—functions that are not fully recapitulated by fibrillar collagens or synthetic scaffolds. Experimental studies show that modification of collagen matrices with hyaluronic acid oligosaccharides accelerates endothelialization and directs cell alignment (Jia et al., 2022), Inspired by this research, it is conceivable that future scaffold designs incorporating hyaluronic acid oligosaccharide modifications could be engineered to enrich or mimic type VIII collagen, thereby providing critical biochemical and topographical cues that facilitate early vascular integration and microvascular pattern formation. In corneal applications, bioengineered matrices and three-dimensional printed constructs incorporating type VIII collagen exhibit excellent biocompatibility and structural fidelity (Orash et al., 2022; Guérin et al., 2021), enabling corneal epithelial and endothelial cells to restore adhesion, polarity, and matrix organization with minimal inflammatory response. Notably, these engineered substitutes more closely reproduce the lattice-like ultrastructure of Descemet’s membrane than conventional collagen hydrogels, highlighting their potential for treating corneal endothelial disorders and postoperative stromal defects. Despite these advances, several challenges hinder clinical translation of COL8-based scaffolds, including the difficulty of recapitulating native post-translational modifications required for proper folding, instability of supramolecular assembly in recombinant systems, and the need for scalable, Good Manufacturing Practice (GMP)–compliant production workflows.

Accumulating evidence suggests that type VIII collagen and its proteolytic fragments may serve as clinically informative biomarkers for disorders marked by extracellular matrix remodeling, dysregulated angiogenesis, or basement membrane injury. Competitive ELISA assays targeting type VIII collagen have revealed significantly elevated serum levels in patients with chronic obstructive pulmonary disease (COPD) and several malignancies, including lung squamous cell carcinoma, breast cancer, and colorectal cancer, whereas no significant change has been observed in idiopathic pulmonary fibrosis. These data support the potential utility of type VIII collagen as a diagnostic and disease-monitoring biomarker in selected cancers, although its value as a surrogate for response to anti-angiogenic therapy remains to be established (Hansen et al., 2016). More recently, COL8-related blood biomarkers have progressed from proof-of-concept studies to cohort-based evaluations of prognostic significance. In cholangiocarcinoma, baseline serum levels of the Col8a1 NC1 domain are significantly higher than those in healthy controls and independently predict overall and progression-free survival. Moreover, an early decline after the first chemotherapy cycle is more frequent among patients achieving stable disease or partial response, indicating potential utility for treatment-response monitoring (Kaps et al., 2025). By contrast, studies in metastatic pancreatic and colorectal cancers indicate that COL8-derived fragments (e.g., C8-C or vastatin) reflect tumor stromal activity but provide limited incremental prognostic value beyond established collagen turnover markers and conventional tumor biomarkers (Wang et al., 2021). In diabetic nephropathy, elevated circulating levels of type VIII collagen degradation products (e.g., C8-C) correlate with disease progression, supporting their use as early indicators of renal injury (Gerth et al., 2007). Despite these promising findings, clinical implementation of COL8-based biomarkers is constrained by insufficient analytical specificity relative to other collagens—particularly types IV and X—highlighting the need for improved assay design and validation.

Therapeutic strategies targeting COL8-related disorders are rapidly advancing and encompass gene editing, cell-based therapies, tissue engineering, biomaterials development, and molecular pharmacology. Gene editing represents the most direct approach for correcting pathogenic Col8a2 variants associated with early-onset Fuchs’ endothelial corneal dystrophy (FECD). CRISPR/Cas9-mediated disruption of mutant start codons has been shown to restore endothelial cell polarity and reduce corneal edema in murine models, demonstrating the feasibility of allele-specific intervention (Uehara et al., 2021). Complementing gene-based approaches, cell therapy has reached early clinical application through transplantation of cultured corneal endothelial cells in combination with Rho kinase inhibitors, with initial trials reporting sustained corneal clarity and low immunogenicity (Okumura et al., 2018). In addition, mesenchymal stem cell–derived exosomes have been shown to deliver anti-inflammatory microRNAs that modulate NF-κB signaling and partially restore COL8 homeostasis, yielding therapeutic benefit in experimental models of COL8-deficient FECD (Liu et al., 2008; Raffetto and Khalil, 2008). At the biomaterials level, recent reviews in corneal bioengineering underscore growing interest in engineered substrates and tissue-engineered alternatives for Descemet membrane endothelial keratoplasty (DMEK), driven primarily by donor tissue shortages (Zwingelberg et al., 2025). Although collagen-based scaffolds for corneal stromal and endothelial repair have been extensively explored (Orash et al., 2022; Namli et al., 2025; Chi et al., 2023; Gingras et al., 2023), no peer-reviewed studies to date have reported type VIII collagen–based scaffolds or three-dimensional printed constructs that recapitulate the native hexagonal lattice of Descemet’s membrane and support durable endothelial function in vitro or in vivo. Despite substantial progress in bioprinting and scaffold engineering, major translational barriers remain, including access to native or recombinant COL8 with appropriate post-translational modifications, reproducible supramolecular assembly, and scalable Good Manufacturing Practice (GMP)–compliant production. Accordingly, COL8-based biomaterials should be regarded as a promising yet unvalidated avenue for future translational research.

Despite growing structural insights into the NC1 domain of type VIII collagen, no pharmacological agents specifically targeting this domain are currently available. To date, the only direct strategy aimed at COL8 involves CRISPR/Cas9-mediated allele disruption in a mouse model of early-onset Fuchs’ endothelial corneal dystrophy (FECD), which effectively arrested endothelial degeneration. Other therapeutic approaches, such as Rho kinase (ROCK) inhibitor–assisted transplantation of ex vivo–expanded corneal endothelial cells, have indirectly restored a COL8-containing basement membrane milieu without directly modulating COL8. Consequently, COL8-directed therapy remains at a nascent stage, with most efforts focused on structural characterization, disease genetics, and proof-of-concept gene editing.

Although interest in type VIII collagen has expanded across diverse pathological contexts—including corneal endothelial disorders, vascular remodeling, and fibrosis—its clinical translation is hindered by several practical challenges. Chief among these is the pronounced context dependence of COL8 function; for example, in atherosclerosis it contributes to plaque stabilization yet may also exacerbate luminal narrowing, necessitating carefully timed and spatially restricted interventions to avoid adverse effects. Moreover, the absence of highly specific COL8 inhibitors constrains pharmacological development, and the structural homology within the collagen superfamily raises concerns about off-target effects. In parallel, the technical difficulty of producing biologically active full-length type VIII collagen limits its scalability for regenerative applications.

Accordingly, future translational advances are unlikely to arise from single-target blockades alone. Instead, emphasis should be placed on precision strategies—such as targeted delivery platforms (e.g., siRNA nanocarriers) and advanced gene-editing technologies—that enable spatiotemporal control of COL8 expression. Key applications, challenges, and prospective directions are summarized in Table 1.