Ping Xin1†
Chengqiao Ge
Bin Fu- 1College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- 2The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
The progression of chronic kidney disease (CKD) is closely associated with damage to the endothelial glycocalyx (eGC) of the renal microvasculature. The eGC, particularly its heparan sulfate (HS) components, is crucial for maintaining the charge-selective barrier and microenvironmental homeostasis. Modern pharmacological investigations of marine brown algae (e.g., Saccharina japonica), traditionally used in medicine for conditions such as “edema,” reveal that their principal active component, fucoidan, is a sulfated polysaccharide with marked physicochemical similarities to endogenous HS. This review systematically posits that the core mechanism underlying the nephroprotective effects of fucoidan, as a natural product, lies in its direct targeting and repair of the damaged eGC. Through a systematic literature search up to November 2025, this review elucidates that fucoidan, especially its low-molecular-weight fractions, can consolidate and reconstitute the glycocalyx structure via dynamic integration, competitive substitution, and activation of intracellular signaling pathways. This central action not only directly restores the renal charge barrier and reduces proteinuria but also, by stabilizing endothelial function, systemically inhibits the inflammation and fibrosis cascades triggered by glycocalyx injury. The efficacy of fucoidan in diverse preclinical models, coupled with clinical trial evidence for fucoidan-based drugs in human CKD patients, collectively supports the validity of a glycocalyx-targeted therapeutic strategy. We conclude that fucoidan represents a natural product derived from traditional wisdom, with a defined molecular mechanism and translational potential, offering a promising complementary strategy for the comprehensive management of CKD.
1 Introduction
Chronic kidney disease (CKD) poses a formidable global public health challenge, affecting over 700 million individuals (Francis et al., 2024). Its progression is characterized by persistent inflammation, oxidative stress, and renal fibrosis (Rayego-Mateos and Valdivielso, 2020). Current standard therapies, predominantly represented by renin-angiotensin system inhibitors (Kalantar-Zadeh et al., 2021; Kidney Disease: Improving Global Outcomes CKD Work Group 2024), often inadequately halt renal fibrosis, underscoring an urgent need for novel strategies. Recent research focus has shifted towards microvascular endothelial dysfunction and its luminal surface layer, the glycocalyx (Ying et al., 2023b). The endothelial glycocalyx is a complex mesh-like structure composed primarily of glycosaminoglycans (e.g., heparan sulfate, HS), proteoglycans, and glycoproteins (Ricard-Blum et al., 2024). In the kidney, particularly within glomerular capillaries, an intact glycocalyx serves as the anatomical basis for the charge-selective barrier, preventing the filtration of anionic proteins like albumin (Masola et al., 2021; Foote et al., 2022), and precisely regulates vascular permeability, inflammatory cell adhesion, and growth factor activity (Dancy et al., 2024; Wong et al., 2024). In CKD, various factors (e.g., hyperglycemia, hypertension, uremic toxins) increase reactive oxygen species (ROS) and inflammatory cytokines, subsequently activating degradative enzymes like heparanase, thereby disrupting the eGC “synthesis-degradation” balance. This leads to glycocalyx shedding, HS loss, and charge barrier collapse, manifesting as proteinuria and further activating potent inflammatory and fibrotic signaling networks. Consequently, repairing the endothelial glycocalyx has emerged as a promising new strategy for renal protection (Ying et al., 2023a; Huang et al., 2020).
Concurrently, traditional medical wisdom provides clues for discovering such therapies (Chen et al., 2023; Cheng and Cheng, 2019). Marine medicinal algae, notably “Haizao” (Sargassum) and “Kunbu” (Laminaria), have a long history of use in China for symptoms like “edema” (Wang, 2011; Chen, 2016; Huang et al., 2015), corresponding to the clinical manifestations of modern kidney diseases (Ren and Wu, 2025). Modern pharmacological studies indicate that fucoidan is a major active constituent common to these herbs, characterized as a sulfated polysaccharide (Zahan et al., 2022; An et al., 2022). Based on its significant protective effects in various renal injury models (Gao et al., 2022; Yu et al., 2020), we propose the core hypothesis of this review: the protective effect of fucoidan against CKD primarily stems from its physicochemical similarity to endogenous HS (Dagälv et al., 2022), enabling it to directly target, integrate into, and repair the damaged renal endothelial glycocalyx, thereby conferring broad renal benefits through the restoration of endothelial homeostasis. This article will systematically integrate existing evidence to elaborate on this mechanism and discuss its clinical implications and future directions. The detailed literature search strategy, including inclusion and exclusion criteria, is provided in the Supplementary Material.
2 Chemical structure, sources, and structure-activity relationship of fucoidan
Fucoidan is a natural sulfated polysaccharide extracted from marine brown algae (Ale et al., 2011). Common sources include various brown algae listed in the Chinese Pharmacopoeia (Chinese Pharmacopoeia Commission, 2020), such as Sargassum pallidum (Turner) C. Agardh (Zhang et al., 2025), Sargassum fusiforme (Harvey) Setchell (Lei et al., 2025), Saccharina japonica (Areschoug) Lane, Mayes, Druehl and Saunders (also known as Laminaria japonica) (Luan et al., 2021), and Ecklonia kurome Okamura (Zha et al., 2015). Its chemical structure is based on a backbone of α-L-fucopyranose residues predominantly linked via α-(1→3) and/or α-(1→4) glycosidic bonds, with sulfate ester groups commonly substituted at the C-2 and/or C-4 positions (Cui et al., 2022).
The biological activity of fucoidan is highly structure-dependent (Li et al., 2020). Its molecular weight (MW) distribution is broad and influenced by algal source and extraction processes. For instance, fucoidan from Saccharina japonica, most commonly used for renal protection, typically has an MW ranging from approximately 7 kDa (Wang et al., 2020) to 2,000 kDa (He et al., 2007). Degradation to low-molecular-weight fucoidan (LMWF, typically <10 kDa) (Xu et al., 2016; Gao et al., 2023) or fucoidan oligosaccharides (typically ∼800 Da) (Yu et al., 2020) generally confers superior renoprotective activity. This is attributed to: (i) improved solubility and reduced steric hindrance, facilitating tissue diffusion and access to cell-surface targets; (ii) enhanced potential for transmembrane transport and cellular internalization, allowing uptake by endothelial cells to modulate intracellular signaling pathways (detailed in Section 3.3); and (iii) favorable pharmacokinetic properties, including better oral absorption and more pronounced renal distribution (detailed in Section 3.4). Sulfate groups confer a polyanionic character to fucoidan. Its degree of sulfation (sulfate content typically ranging from 6.01% to 38.3%) (Hamouda et al., 2025) directly correlates with its negative charge density. High sulfation effectively mimics the electrostatic properties of endogenous HS, providing the chemical basis for strong electrostatic interactions with HS-binding proteins, such as growth factors, enzymes, and the heparin-binding domains (HBDs) on glycocalyx core proteins (Bilan et al., 2017; Yue et al., 2025). This structural similarity is the prerequisite for its ability to target and integrate into damaged glycocalyx sites. Furthermore, fucoidans from different sources may contain other monosaccharides (e.g., galactose, xylose, glucuronic acid) and vary in chain branching and linkage patterns, potentially affecting their binding specificity and affinity for particular protein targets.
3 Direct protection and repair of the endothelial glycocalyx by fucoidan
3.1 Role of the endothelial glycocalyx in renal physiology and pathology
The endothelial glycocalyx of glomerular capillaries, especially its abundant HS side chains (Masola et al., 2021), forms the primary basis of the glomerular charge barrier, electrostatically repelling anionic proteins like albumin (Prasad et al., 2025). It also functions as a dynamic signaling platform that precisely regulates vascular tone, inflammatory responses, and tissue repair by binding and modulating growth factors, enzymes, and chemokines (Dancy et al., 2024; Wong et al., 2024). During CKD progression, multiple pathological factors (e.g., hyperglycemia, hypertension, uremic toxins) synergistically induce excessive reactive oxygen species (ROS) production and promote the release of inflammatory cytokines like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) (Lepedda et al., 2017). This upregulates the expression and activity of degradative enzymes, including heparanase (HPSE) and matrix metalloproteinases (MMPs) (Buijsers et al., 2023; Haddad et al., 2015; Patterson et al., 2022). HPSE, the key rate-limiting enzyme cleaving HS chains, is central to enzymatic glycocalyx degradation, directly causing extensive shedding, significant HS loss, and charge barrier collapse. Such structural damage, confirmed by transmission electron microscopy in CKD animal models and human kidney specimens, is evidenced by a marked reduction in the thickness and density of the peritubular capillary glycocalyx (Ermert et al., 2023). Elevated levels of circulating glycocalyx degradation products (e.g., soluble syndecan-1, hyaluronan) (Yuan et al., 2022) correlate positively with clinical disease severity. In clinical studies, these markers are associated with increased urinary albumin-to-creatinine ratio (UACR), elevated systemic inflammatory markers (e.g., IL-6, TNF-α), faster decline in estimated glomerular filtration rate (eGFR), and increased cardiovascular event risk (Kim et al., 2017).
Among various pathogenic factors, protein-bound uremic toxins, notably indoxyl sulfate (IS), are considered key drivers of glycocalyx injury due to their significant accumulation in renal impairment and direct attack on endothelial cells. The molecular mechanism is increasingly elucidated: IS activates endothelial NADPH oxidase (particularly the Nox4 subunit), induces mitochondrial dysfunction and excessive ROS production, and subsequently activates the ERK/p38 mitogen-activated protein kinase (MAPK)–nuclear factor-kappa B (NF-κB) signaling pathway. This upregulates the expression of pro-inflammatory factors like monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) and promotes HPSE release, thereby accelerating HS degradation (Masai et al., 2010).
Therefore, endothelial glycocalyx injury is both an early structural marker of microvascular pathology in CKD and a critical pathological link driving proteinuria and subsequent inflammatory-fibrotic cascades. Dynamic changes in circulating glycocalyx components not only reflect the extent of endothelial injury but also offer a potential biomarker window for non-invasive monitoring of disease activity and endothelial health.
3.2 Immediate repair of the charge barrier
Facing the exposed, positively charged HBDs of core proteins (e.g., syndecan-1) following HS loss (Jiang et al., 2021; Diab et al., 2024), fucoidan executes immediate, dynamic integration based on its striking physicochemical similarity to endogenous HS (Kuo et al., 2019). The essence of this action is structure-based competitive functional substitution. The high-density sulfate groups on the fucoidan backbone render it a strong polyanion. Through precise electrostatic interactions (notably salt bridge formation with arginine residues in HBDs) and hydrogen bonding networks (Li et al., 2025), fucoidan reversibly yet with high affinity anchors at injury sites. Biophysical studies support the existence of such specific interactions (Kabedev and Lobaskin, 2022). Additionally, specific molecular recognition mechanisms (e.g., CH-π interactions) between fucose units and proteins may further facilitate this integration (Zhu et al., 2024). This immediate competitive integration rapidly restores local glycocalyx negative charge density and molecular sieve properties. In vitro experiments and animal models (Xu et al., 2016; Xue et al., 2025; Yu et al., 2020) confirm that low-molecular-weight fucoidan (LMWF) or oligo-fucoidan significantly reduces endothelial albumin permeability induced by inflammatory factors, with superior effects compared to high-MW fucoidan (Tan et al., 2020). This mechanism was directly validated in the passive Heymann nephritis model, a model of secondary glycocalyx injury (Zhang et al., 2005), where proteinuria was linked to HS reduction in the glomerular basement membrane (GBM) attributed to complement-mediated cleavage, ultimately increasing GBM permeability to macromolecules. That study directly observed that fucoidan restored glomerular charge selectivity, corroborating its core mechanism of mimicking HS and competitively integrating into damaged sites to restore filtration barrier function.
3.3 PI3K/Akt and ERK/MAPK signaling pathway-mediated active glycocalyx repair
Fucoidan’s action on the eGC extends beyond mere physical substitution, involving bidirectional active regulation of its metabolism, primarily manifesting in inhibiting degradation and promoting synthesis. Regarding degradation inhibition, fucoidan, as an HS structural analog, can competitively inhibit the activity of the key degrading enzyme HPSE. Its inhibitory potency correlates positively with the degree of sulfation, with fully sulfated derivatives showing the strongest inhibitory capacity (Sugimoto et al., 2025; Mo et al., 2025). Concerning synthesis promotion and repair, fucoidan activates specific intracellular signaling pathways in endothelial cells, mobilizing cellular regeneration programs. Studies show that fucoidan activates pro-survival and anabolic signaling pathways such as phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and extracellular signal-regulated kinase (ERK)/MAPK (Regier et al., 2022). Pathway activation stimulates the Golgi vesicular system to transport pre-synthesized glycocalyx components (e.g., syndecan-1) to the cell surface for rapid replenishment (Regier et al., 2022). It may also promote the transcription of glycocalyx synthesis-related genes (e.g., HS synthesis enzymes EXT1, EXT2) (Haddad et al., 2015), supporting de novo synthesis and long-term reconstruction. Furthermore, antioxidant pathways (e.g., nuclear factor erythroid 2–related factor 2, Nrf2) activated by fucoidan upregulate cytoprotective genes like heme oxygenase-1 (HO-1), providing a favorable microenvironment for glycocalyx synthesis by mitigating oxidative stress (Yu et al., 2020). Thus, fucoidan achieves multi-level, active repair of glycocalyx homeostasis by coordinately regulating synthesis-promoting and degradation-inhibiting genes.
3.4 Pharmacokinetics, biodistribution, and administration routes
Effective delivery of fucoidan, particularly LMWF, to renal targets is a prerequisite for its renoprotective action. Pharmacokinetic studies support its renal tropism. Animal experiments indicate that after oral or intravenous administration, LMWF accumulates more rapidly and reaches higher concentrations in the kidneys compared to organs like the heart and brain (Wang, 2014; Tan, 2020). Although oral bioavailability reports vary, it is generally considered low (e.g., 2.67%, time to peak ∼2 h, plasma concentration ∼7.33 μg/mL) (Chu, 2017). This limited absorption and subsequent renal distribution are related to LMWF’s improved intestinal absorption via clathrin-mediated endocytosis and its renal filtration and/or binding characteristics (Chu, 2017). Human studies further confirm that low-MW fragments of fucoidan are detectable in urine after oral ingestion by healthy volunteers, providing direct evidence for its absorption and renal delivery in humans (Kadena et al., 2018; Rocha Amorim et al., 2016).
Regarding administration routes, the oral route is primary for approved formulations (e.g., Haikun Shenxi Capsule) (He et al., 2007). Orally administered LMWF is partially absorbed, and its renoprotective effects likely result from a combination of direct systemic effects and indirect effects via gut microbiota modulation (see Section 4). Oral administration offers high compliance, suitable for long-term CKD management. Intravenous administration, while ensuring complete bioavailability and rapid onset—potentially applicable for acute kidney injury—remains investigational, lacking marketed formulations. Preclinical studies suggest a need for cautious safety evaluation, as intravenous administration may significantly prolong clotting time, posing a potential bleeding risk (Sun et al., 2025). Therefore, for the chronic management of CKD, oral administration is currently the more practical and sustainable choice. Future efforts should include head-to-head clinical studies comparing efficacy and safety across routes and exploring nanomaterial-based targeted delivery systems or developing structurally defined, activity-controlled intravenous derivatives (e.g., synthetic fucoidans with selective anticoagulant activity) to overcome intravenous administration bottlenecks.
4 Interaction between glycocalyx repair and core CKD pathological networks
By repairing the glycocalyx via the aforementioned mechanisms, fucoidan systematically intervenes in the core pathological mechanisms of CKD—oxidative stress, inflammation, and fibrosis—forming a virtuous cycle (Figure 1).
Figure 1. Fucoidan as a Renal Protectant by Targeting the Endothelial Glycocalyx. Note: Light green = normal endothelial glycocalyx, grey = injured endothelial glycocalyx, golden yellow = fucoidan.
In countering oxidative stress, fucoidan activates the cytoprotective transcription factor Nrf2, causing its dissociation from Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation, upregulating the expression of phase II detoxifying enzymes and antioxidant proteins like HO-1 (Yu et al., 2020). This directly scavenges ROS, a key attacker causing glycocalyx degradation, thereby protecting glycocalyx integrity and breaking the vicious cycle of “ROS damages glycocalyx–glycocalyx shedding exacerbates oxidative stress.”
In suppressing the inflammatory cascade, an intact glycocalyx is a physical barrier inhibiting leukocyte adhesion. Fucoidan, by repairing the glycocalyx, directly reduces the initiation of leukocyte rolling and adhesion. Concurrently, it effectively downregulates the production of pro-inflammatory cytokines like TNF-α and IL-6 by inhibiting Toll-like receptor 4 (TLR4) and its downstream NF-κB signaling pathway (Wang et al., 2015; Xu et al., 2016). Notably, NF-κB activation itself upregulates glycocalyx-degrading enzymes like HPSE (Xu et al., 2025); thus, fucoidan’s anti-inflammatory action also indirectly inhibits further glycocalyx destruction.
In curbing the fibrotic process, an intact glycocalyx binds and modulates the bioactivity of pro-fibrotic factors like transforming growth factor-β (TGF-β). Fucoidan-mediated glycocalyx repair restores spatial sequestration and regulation of TGF-β signaling. Moreover, its anti-inflammatory and antioxidant effects collectively create a microenvironment inhibiting myofibroblast activation and excessive extracellular matrix deposition. Studies also indicate that fucoidan can directly downregulate pro-fibrotic signaling pathways such as TGF-β/Smad and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) (Chen et al., 2017; Sun et al., 2023).
Additionally, there are other synergistic protective effects. As dietary fiber, fucoidan enriches probiotics (e.g., Akkermansia muciniphila; Wang Z et al., 2025); the short-chain fatty acids (primarily acetate) produced by their fermentation enter circulation and can inhibit renal TLR4 signaling, alleviating inflammation and fibrosis (Zhong et al., 2024; Wang Y. et al., 2025). By activating pathways like Nrf2 and solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4), fucoidan inhibits ROS accumulation and ferroptosis, protecting renal tubular epithelial cells (Chen S. et al., 2025; Cao et al., 2025). Fucoidan improves mitochondrial function (Shi et al., 2025; Veena et al., 2008), activates mitophagy (Gao et al., 2023; Shi et al., 2025), and ameliorates metabolic disturbances like insulin resistance (Xue et al., 2025; Peng et al., 2020), further enhancing renal protection.
5 Translational evidence: validation from preclinical models to human efficacy
Numerous preclinical studies have consistently demonstrated the renoprotective effects of fucoidan (especially LMWF) across diverse renal injury models. These models encompass CKD (Wang et al., 2012; Chen et al., 2021; Ma et al., 2022; Li et al., 2017; Katai et al., 2015), renal fibrosis (Sun et al., 2023), nephrotic syndrome (Tan et al., 2020), hyperuricemia (Xue et al., 2024), hyperoxaluria (Veena et al., 2006a; Veena et al., 2006b), metabolic-related injuries like diabetic kidney disease (Cai et al., 2024; Xu et al., 2021; Wang et al., 2021; Wang et al., 2014), and acute or immune-mediated injury models such as ischemia-reperfusion, drug toxicity, and Heymann nephritis (Shu et al., 2021; Jiang et al., 2025; Zhao et al., 2007). Studies commonly report that fucoidan (especially low-MW fractions) significantly reduces proteinuria, improves renal function (e.g., lowering serum creatinine and blood urea nitrogen), alleviates histopathological damage (e.g., glomerulosclerosis, tubular injury, interstitial fibrosis), and downregulates inflammatory and oxidative stress markers.
However, key preclinical studies summarized in Table 1 reveal inherent limitations. First, most animal models (especially acute kidney injury models) fail to fully replicate the complex course and heterogeneity of human CKD. Second, there is significant methodological heterogeneity and underreporting; many studies do not fully characterize the test material’s chemical profile (e.g., MW, degree of sulfation, purity), hindering direct comparison of pharmacological activity and outcomes across fucoidans from different sources. Furthermore, some studies have small sample sizes, and only a few have conducted systematic multi-dose explorations, affecting conclusion reliability and generalizability. These factors collectively limit direct inter-study comparisons and extrapolation of findings. Consequently, future preclinical research priorities should include: (1) Standardized Reporting: Mandating detailed description of fucoidan’s key chemical parameters (especially MW) and animal experiment randomization/blinding procedures; (2) Improved Models: Greater use of models simulating the chronic progression of human CKD; (3) Elucidation of Dose-Response Relationships: Fundamental for confirming efficacy and safety.
Table 1. Representative preclinical studies on the protective effects of fucoidan in kidney diseases.
Despite these limitations, the efficacy of fucoidan has translated into clinical benefit. Drugs primarily containing fucoidan (e.g., Haikun Shenxi Capsule) have shown significant efficacy in multiple clinical studies (including randomized controlled trials and observational studies) targeting chronic renal insufficiency (Yu, 2025; Sun et al., 2025), chronic renal failure (Zhang, 2023; Cai et al., 2024; Zhang, 2024; Liu et al., 2023), diabetic kidney disease (from early stages to dialysis) (Zhang, 2025; Zhang et al., 2025; Liu et al., 2023; Shi et al., 2023; Dong and Li, 2022; Dong and Qin, 2023; Liu, 2023), and chronic glomerulonephritis (Zhu, 2023; Liu, 2022), whether used alone or in combination with conventional Western medicines (e.g., renin-angiotensin system inhibitors, liraglutide). The clinically observed significant reduction in proteinuria (manifested as decreased 24-h urine protein or UACR) is key indirect evidence of improved endothelial charge barrier and structural function. Simultaneously, the downregulation of circulating inflammatory markers (e.g., C-reactive protein, IL-6, TNF-α) reflects reduced endothelial activation and systemic inflammation. Multiple studies consistently report decreased serum creatinine and blood urea nitrogen levels, as well as stabilization or improvement in eGFR or creatinine clearance, directly demonstrating improved overall renal function and delayed CKD progression.
Regarding safety, existing clinical studies (mostly weeks to months) report adverse events primarily as mild, reversible gastrointestinal discomfort, with incidence rates not significantly different from conventional treatment groups, indicating good short-term tolerability. However, the long-term (years) safety of fucoidan (especially oral LMWF products) requires confirmation via longer follow-up studies. Particular attention should be paid to its inherent, heparin-like anticoagulant and antiplatelet activity (Chen X. et al., 2025): in advanced CKD patients who often have coagulation abnormalities and may be on antithrombotic agents, long-term supplementation could interfere with coagulation balance and increase bleeding risk. Current human studies have not identified clear negative clinical consequences on immune surveillance, extracellular matrix turnover, or vascular remodeling, but these theoretical possibilities warrant monitoring in long-term studies.
In summary, existing clinical evidence provides real-world support for fucoidan’s renoprotective effects via endothelial protection mechanisms. However, current evidence is largely based on specific compound formulations and Chinese populations. Future international, multicenter, large-scale, long-term follow-up randomized controlled trials are needed to validate the universal efficacy and long-term safety of fucoidan from different sources. Such studies should systematically incorporate safety endpoints including coagulation parameters and bleeding events and strive to integrate more direct methods for assessing endothelial function and glycocalyx status to further consolidate its clinical application.
6 Discussion and future perspectives
This review establishes that targeting, protecting, and repairing the endothelial glycocalyx is the central hub mechanism through which fucoidan exerts its renoprotective effects. This mechanism tightly links structural repair with functional improvement, providing a clear logic for pathological intervention. Looking forward, in-depth research and clinical translation in this field should focus on several key levels. First, regarding the mechanism of action, advanced techniques such as surface plasmon resonance (SPR) (Wang et al., 2020), isothermal titration calorimetry (ITC), and cell-specific gene editing should be employed to precisely quantify the interaction between fucoidan and glycocalyx components and validate its key cellular targets in vivo. Concurrently, structure-activity relationships need systematic elucidation to guide the rational design of next-generation, highly effective and specific derivatives. Second, in clinical translation, given that current clinical evidence mainly originates from specific formulations and populations, there is an urgent need for international, multicenter, large-scale, long-term follow-up randomized controlled trials to validate its efficacy and safety globally and explore its synergistic potential with existing standard therapies (e.g., sodium-glucose cotransporter-2 inhibitors). Finally, in the diagnostic and therapeutic paradigm, the endothelial glycocalyx itself shows great potential as a bridge connecting mechanism and clinical phenotype: circulating glycocalyx components could serve as dynamic biomarkers for early risk stratification, monitoring disease activity, and acting as “pharmacodynamic biomarkers” for intervention efficacy. Although establishing them as formal surrogate endpoints requires more prospective evidence, this undoubtedly represents a highly promising research direction. In conclusion, fucoidan represents a treatment candidate rooted in tradition with a novel mechanism. Through prudent scientific investigation and rigorous clinical validation, it holds promise as an important complementary strategy for the comprehensive management of CKD.
Author contributions
PX: Conceptualization, Writing – original draft, Writing – review and editing. CG: Conceptualization, Writing – original draft, Writing – review and editing. YT: Data curation, Writing – review and editing. YH: Data curation, Writing – review and editing. BF: Conceptualization, Methodology, Supervision, Writing – review and editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgements
The authors would like to thank all co-authors for their invaluable assistance in the preparation of this manuscript.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2026.1749109/full#supplementary-material
References
Ale, M. T., Mikkelsen, J. D., and Meyer, A. S. (2011). Important determinants for fucoidan bioactivity: a critical review of structure-function relations and extraction methods for fucose-containing sulfated polysaccharides from brown seaweeds. Mar. Drugs 9 (10), 2106–2130. doi:10.3390/md9102106
An, E. K., Hwang, J., Kim, S. J., Park, H. B., Zhang, W., Ryu, J. H., et al. (2022). Comparison of the immune activation capacities of fucoidan and laminarin extracted from laminaria japonica. Int. J. Biol. Macromol. 208, 230–242. doi:10.1016/j.ijbiomac.2022.03.122
Bilan, M. I., Ustyuzhanina, N. E., Shashkov, A. S., Thanh, T. T. T., Bui, M. L., Tran, T. T. V., et al. (2017). Sulfated polysaccharides of the Vietnamese brown alga Sargassum aquifolium (fucales, sargassaceae). Carbohydr. Res. 449, 23–31. doi:10.1016/j.carres.2017.06.016
Buijsers, B., Garsen, M., de Graaf, M., Bakker-van Bebber, M., Guo, C., Li, X., et al. (2023). Heparanase-2 protein and peptides have a protective effect on experimental glomerulonephritis and diabetic nephropathy. Front. Pharmacol. 14, 1098184. doi:10.3389/fphar.2023.1098184
Cai, H., Xu, C., Chen, L. Y., Li, J., Sun, Q., and Liang, M. (2024). Clinical value analysis of shenqi dihuang decoction combined with haikun shenxi capsules in the treatment of patients with chronic renal failure. Chin. J. Integr. Traditional West. Nephrol. 25 (10), 906–908.
Cao, Y., Liu, X., Guo, C., Yang, W., Wang, X., Wang, X., et al. (2025). Biomimetic reactive oxygen/nitrogen nanoscavengers inhibit ferroptosis storm and modulate immune targeting for acute kidney injury. J. Control Release 379, 59–76. doi:10.1016/j.jconrel.2025.01.006
Chen, S. G. (2016). Wai Ke zheng zong (the Orthodox manual of surgery). Beijing: People's Medical Publishing House.
Chen, C. H., Sue, Y. M., Cheng, C. Y., Chen, Y. C., Liu, C. T., Hsu, Y. H., et al. (2017). Oligo-fucoidan prevents renal tubulointerstitial fibrosis by inhibiting the CD44 signal pathway. Sci. Rep. 7, 40183. doi:10.1038/srep40183
Chen, Y. C., Cheng, C. Y., Liu, C. T., Sue, Y. M., Chen, T. H., Hsu, Y. H., et al. (2021). Combined protective effects of oligo-fucoidan, fucoxanthin, and L-carnitine on the kidneys of chronic kidney disease mice. Eur. J. Pharmacol. 892, 173708. doi:10.1016/j.ejphar.2020.173708
Chen, J., Liu, K., Zhang, W., and Zhao, L. H. (2023). Research on the main diseases and syndromes of the ancient medical use of the iodine-rich medicine pair Kunbu-Haizao. Clin. J. Traditional Chin. Med. (07), 1298–1304. doi:10.16448/j.cjtcm.2023.0712
Chen S, S. C., Qin, X., Xiong, N., Lin, L., Wu, Y., Li, Q., et al. (2025). Comprehensive synthesis and anticoagulant evaluation of a diverse fucoidan library. Nat. Commun. 16 (1), 4364. doi:10.1038/s41467-025-59632-2
Chen X, X., Niu, B., Zhang, Z., Zhang, B., Xue, T., Liu, Y., et al. (2025). Low-molecular-weight fucoidan ameliorates ferroptosis in diabetic kidney disease through SLC7A11/GSH/GPX4 activation. Fitoterapia 185, 106779. doi:10.1016/j.fitote.2025.106779
Cheng, H. W., and Cheng, X. P. (2019). Summary of yan Xiaoping's experience in treating diabetic nephropathy from the spleen. Shaanxi J. Traditional Chin. Med. (06), 790–792. doi:10.19347/j.cnki.2096-1413.202121006
Chinese Pharmacopoeia Commission (2020). Pharmacopoeia of the People'S Republic of China, part I, 267–268. Beijing: China Medical Science and Technology Press.
Chu, F. L. (2017). Intestinal absorption and preliminary pharmacokinetic study of fucoidan. Jinan, China: Shandong University.
Cui, J., Wang, Y., Kim, E., Zhang, C., Zhang, G., and Lee, Y. (2022). Structural characteristics and immunomodulatory effects of a long-chain polysaccharide from laminaria japonica. Front. Nutr. 9, 762595. doi:10.3389/fnut.2022.762595
Dagälv, A., Lundequist, A., Filipek-Górniok, B., Dierker, T., Eriksson, I., and Kjellén, L. (2022). Heparan sulfate structure: methods to study N-Sulfation and NDST action. Methods Mol. Biol. 2303, 139–150. doi:10.1007/978-1-0716-1398-6_12
Dancy, C., Heintzelman, K. E., and Katt, M. E. (2024). The glycocalyx: the importance of sugar coating the blood-brain barrier. Int. J. Mol. Sci. 25 (15), 8404. doi:10.3390/ijms25158404
Diab, L., Al Kattar, S., Oueini, N., Hawi, J., Chrabieh, A., Dosh, L., et al. (2024). Syndecan-1: a key player in health and disease. Immunogenetics 77 (1), 9. doi:10.1007/s00251-024-01366-4
Dong, L., and Li, W. J. (2022). Effect of huangkui capsules combined with haikun shenxi in the treatment of patients with chronic kidney disease. Guide China Med. 20 (26), 105–107. doi:10.15912/j.cnki.gocm.2022.26.052
Dong, L., and Qin, F. H. (2023). Clinical observation on adjuvant treatment of diabetic nephropathy with renal insufficiency by haikun shenxi capsules. J. Pract. Traditional Chin. Med. 39 (01), 108–110.
Ermert, K., Buhl, E. M., Klinkhammer, B. M., Floege, J., and Boor, P. (2023). Reduction of endothelial glycocalyx on peritubular capillaries in chronic kidney disease. Am. J. Pathol. 193 (2), 138–147. doi:10.1016/j.ajpath.2022.11.003
Foote, C. A., Soares, R. N., Ramirez-Perez, F. I., Ghiarone, T., Aroor, A., Manrique-Acevedo, C., et al. (2022). Endothelial glycocalyx. Compr. Physiol. 12 (4), 3781–3811. doi:10.1002/cphy.c210029
Francis, A., Harhay, M. N., Ong, A. C. M., Tummalapalli, S. L., Ortiz, A., Fogo, A. B., et al. (2024). Chronic kidney disease and the global public health agenda: an international consensus. Nat. Rev. Nephrol. 20 (7), 473–485. doi:10.1038/s41581-024-00820-6
Gao, X., Wang, J., Wang, Y., Liu, S., Dong, K., Wu, J., et al. (2022). Fucoidan-ferulic acid nanoparticles alleviate cisplatin-induced acute kidney injury by inhibiting the cGAS-STING pathway. Int. J. Biol. Macromol. 223 (Pt A), 1083–1093. doi:10.1016/j.ijbiomac.2022.11.062
Gao, X., Yin, Y., Liu, S., Dong, K., Wang, J., and Guo, C. (2023). Fucoidan-proanthocyanidins nanoparticles protect against cisplatin-induced acute kidney injury by activating mitophagy and inhibiting mtDNA-cGAS/STING signaling pathway. Int. J. Biol. Macromol. 245, 125541. doi:10.1016/j.ijbiomac.2023.125541
Haddad, O., Guyot, E., Marinval, N., Chevalier, F., Maillard, L., Gadi, L., et al. (2015). Heparanase and Syndecan-4 are involved in low molecular weight fucoidan-induced angiogenesis. Mar. Drugs 13 (11), 6588–6608. doi:10.3390/md13116588
Hamouda, H. I., Li, T., Shabana, S., Hashem, A. H., and Yin, H. (2025). Advances in fucoidan and fucoidan oligosaccharides: current status, future prospects, and biological applications. Carbohydr. Polym. 358, 123559. doi:10.1016/j.carbpol.2025.123559
He, Y. H., Wang, Q. K., Zhang, T., and Shi, Y. F. (2007). Enzymatic hydrolyzing technology and isolation of fucoidan from laminaria japonica. J. Shenyang Agric. Univ. (02), 215–219.
Huang, Y. Y., and Qing, D.Yu Qiu Yao Jie (Jade Scoop Medicinal Explanations (2015). Beijing: China Press of Traditional Chinese Medicine.
Huang, Y. T., Pan, Y., Jiang, Y. J., and Zhao, J. (2020). Injury and protection of vascular endothelial glycocalyx in a rat model of hindlimb venous hypertension. Chin. J. Vasc. Surg. 42–46. doi:10.27307/d.cnki.gsjtu.2020.002367
Jiang, W., Wang, X., Geng, X., Gu, Y., Guo, M., Ding, X., et al. (2021). Novel predictive biomarkers for acute injury superimposed on chronic kidney disease. Nefrol. Engl. Ed. 41 (2), 165–173. doi:10.1016/j.nefroe.2021.05.001
Jiang, T., Zhu, F., Gao, X., Wu, X., Zhu, W., and Guo, C. (2025). Naringenin loaded fucoidan/polyvinylpyrrolidone nanoparticles protect against folic acid induced acute kidney injury in vitro and in vivo. Colloids Surf. B Biointerfaces 245, 114343. doi:10.1016/j.colsurfb.2024.114343
Kabedev, A., and Lobaskin, V. (2022). Endothelial glycocalyx permeability for nanoscale solytes. Nanomedicine (Lond) 17 (13), 979–996. doi:10.2217/nnm-2021-0367
Kadena, K., Tomori, M., Iha, M., and Nagamine, T. (2018). Absorption study of mozuku fucoidan in Japanese volunteers. Mar. Drugs 16 (8), 254. doi:10.3390/md16080254
Kalantar-Zadeh, K., Jafar, T. H., Nitsch, D., Neuen, B. L., and Perkovic, V. (2021). Chronic kidney disease. Lancet 398 (10302), 786–802. doi:10.1016/S0140-6736(21)00519-5
Katai, K., Iwamoto, A., Kimura, Y., Oshima, Y., Arioka, S., Morimi, Y., et al. (2015). Wakame(Undaria pinnatifida)modulates hyperphosphatemia in a rat model of chronic renal failure. J. Med. Investig. 62 (1-2), 68–74. doi:10.2152/jmi.62.68
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group, 2024 (2024). KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 105 (4S), S117–S314. doi:10.1016/j.kint.2023.10.018
Kim, Y. H., Nijst, P., Kiefer, K., and Tang, W. H. (2017). Endothelial glycocalyx as biomarker for cardiovascular diseases: mechanistic and clinical implications. Curr. Heart Fail. Rep. 14 (2), 117–126. doi:10.1007/s11897-017-0320-5
Kuo, C. W., Chen, H. L., Tu, M. Y., and Chen, C. M. (2019). Serum and urinary SOD3 in patients with type 2 diabetes: comparison with early chronic kidney disease patients and association with development of diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 316 (1), F32–F41. doi:10.1152/ajprenal.00401.2017
Lei, Z., Qin, X., Yang, Y., Xu, M., and Zeng, N. (2025). Recent advances of Sargassum pallidum in chemical and biological aspects. Front. Pharmacol. 16, 1492671. doi:10.3389/fphar.2025.1492671
Lepedda, A. J., De Muro, P., Capobianco, G., and Formato, M. (2017). Significance of urinary glycosaminoglycans/proteoglycans in the evaluation of type 1 and type 2 diabetes complications. J. Diabetes Complicat. 31 (1), 149–155. doi:10.1016/j.jdiacomp.2016.10.013
Li, S., Li, J., Shi, F., Yang, L., and Ye, M. (2017). Protection effect of intracellular melanin from lachnum YM156 and haikunshenxi capsule combination on adenine-induced chronic renal failure in mice. Medchemcomm 8 (5), 917–923. doi:10.1039/c6md00646a
Li, X., Wu, N., Chen, Y., Tan, J., Wang, J., Geng, L., et al. (2020). Degradation of different molecular weight fucoidans and their inhibition of TGF-β1 induced epithelial-mesenchymal transition in mouse renal tubular epithelial cells. Int. J. Biol. Macromol. 151, 545–553. doi:10.1016/j.ijbiomac.2020.02.068
Li, R., Tai, M. R., Su, X. N., Ji, H. W., Chen, J. P., Liu, X. F., et al. (2025). Insights into the mechanism underpinning composite molecular docking during the self-assembly of fucoidan biopolymers with peptide nanofibrils. Mar. Drugs 23 (4), 169. doi:10.3390/md23040169
Liu, J. W. (2022). Clinical observation of haikun shenxi capsules combined with benazepril in the treatment of chronic glomerulonephritis. J. Pract. Traditional Chin. Med. 38 (08), 1319–1321.
Liu, F. Y. (2023). Effect of haikun shenxi capsules combined with benazepril in diabetic nephropathy patients undergoing hemodialysis. Chin. J. Med. Care People's Health 35 (14), 94–96.
Liu, Y. R., Huang, L. Y., Wu, B. X., Liu, S. J., and Chen, Y. X. (2023). Effects of shenqi dihuang decoction combined with haikun shenxi capsules on renal function and oxidative stress in patients with chronic renal failure. China Foreign Med. Treat. 42 (28), 1–4. doi:10.16662/j.cnki.1674-0742.2023.28.001
Luan, F., Zou, J., Rao, Z., Ji, Y., Lei, Z., Peng, L., et al. (2021). Polysaccharides from laminaria japonica: an insight into the current research on structural features and biological properties. Food Funct. 12 (10), 4254–4283. doi:10.1039/d1fo00311a
Ma, Z., Yang, Z., Feng, X., Deng, J., He, C., Li, R., et al. (2022). The emerging evidence for a protective role of fucoidan from laminaria japonica in chronic kidney disease-triggered cognitive dysfunction. Mar. Drugs 20 (4), 258. doi:10.3390/md20040258
Masai, N., Tatebe, J., Yoshino, G., and Morita, T. (2010). Indoxyl sulfate stimulates monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells by inducing oxidative stress through activation of the NADPH oxidase-nuclear factor-κB pathway. Circulation J. 74 (10), 2216–2224. doi:10.1253/circj.cj-10-0117
Masola, V., Zaza, G., Arduini, A., Onisto, M., and Gambaro, G. (2021). Endothelial glycocalyx as a regulator of fibrotic processes. Int. J. Mol. Sci. 22 (6), 2996. doi:10.3390/ijms22062996
Mo, Y., Song, G., Fu, L., Wang, Y., Geng, T., Sun, A., et al. (2025). Low-molecular-weight dextran sulfate sodium as novel heparanase inhibitor preventing breast cancer metastasis in mice by inhibiting migration and angiogenesis. Carbohydr. Polym. 369, 124255. doi:10.1016/j.carbpol.2025.124255
National Pharmacopoeia Committee (2020). Pharmacopoeia of the People'S Republic of China, part I, 267–268. Beijing: China Medical Science and Technology Press.
Patterson, E. K., Cepinskas, G., and Fraser, D. D. (2022). Endothelial glycocalyx degradation in critical illness and injury. Front. Med. (Lausanne) 9, 898592. doi:10.3389/fmed.2022.898592
Peng, Y., Ren, D., Song, Y., Hu, Y., Wu, L., Wang, Q., et al. (2020). Effects of a combined fucoidan and traditional Chinese medicine formula on hyperglycaemia and diabetic nephropathy in a type II diabetes mellitus rat model. Int. J. Biol. Macromol. 147, 408–419. doi:10.1016/j.ijbiomac.2019.12.201
Prasad, R. M., Bali, A., and Tikaria, R. (2025). “Microalbuminuria,” in StatPearls (Treasure Island (FL): StatPearls Publishing).
Rayego-Mateos, S., and Valdivielso, J. M. (2020). New therapeutic targets in chronic kidney disease progression and renal fibrosis. Expert Opin. Ther. Targets 24 (7), 655–670. doi:10.1080/14728222.2020.1762173
Regier, M., Drost, C. C., Rauen, M., Pavenstädt, H., Rovas, A., Kümpers, P., et al. (2022). A dietary supplement containing fucoidan preserves endothelial glycocalyx through ERK/MAPK signaling and protects against damage induced by CKD serum. Int. J. Mol. Sci. 23 (24), 15520. doi:10.3390/ijms232415520
Ren, Y., and Wu, Z. C. (2025). Treatment of renal proteinuria based on the theory of simultaneous treatment of spleen and kidney. Asia-Pacific Tradit. Med. (10), 125–129.
Ricard-Blum, S., Vivès, R. R., Schaefer, L., Götte, M., Merline, R., Passi, A., et al. (2024). A biological guide to glycosaminoglycans: current perspectives and pending questions. FEBS J. 291 (15), 3331–3366. doi:10.1111/febs.17107
Rocha Amorim, M. O., Lopes Gomes, D., Dantas, L. A., Silva Viana, R. L., Chiquetti, S. C., Almeida-Lima, J., et al. (2016). Fucan-coated silver nanoparticles synthesized by a green method induce human renal adenocarcinoma cell death. Int. J. Biol. Macromol. 93 (Pt A), 57–65. doi:10.1016/j.ijbiomac.2016.08.043
Shi, S. H., Gao, H. Y., and Lin, Z. M. (2023). Effects of haikun shenxi capsules combined with valsartan on cytokines, transforming growth factor, matrix metalloproteinase and renal function in elderly patients with early diabetic nephropathy. Diabetes New World 26 (06), 166–169. doi:10.16658/j.cnki.1672-4062.2023.06.166
Shi, J., Xu, Y., Zhang, K., Liu, Y., Zhang, N., Zhang, Y., et al. (2025). Fucoidan oligosaccharide supplementation relieved kidney injury and modulated intestinal homeostasis in D-Galactose-Exposed rats. Nutrients 17 (2), 325. doi:10.3390/nu17020325
Shu, G., Lu, C., Wang, Z., Du, Y., Xu, X., Xu, M., et al. (2021). Fucoidan-based micelles as P-selectin targeted carriers for synergistic treatment of acute kidney injury. Nanomedicine 32, 102342. doi:10.1016/j.nano.2020.102342
Sugimoto, A., Koike, T., Kuboki, Y., Komaba, S., Kosono, S., Aswathy, M., et al. (2025). Synthesis of low-molecular-weight fucoidan analogue and its inhibitory activities against heparanase and SARS-CoV-2 infection. Angew. Chem. Int. Ed. Engl. 64 (6), e202411760. doi:10.1002/anie.202411760
Sun, L., Liu, Q., Zhang, Y., Xue, M., Yan, H., Qiu, X., et al. (2023). Fucoidan from Saccharina japonica alleviates hyperuricemia-induced renal fibrosis through inhibiting the JAK2/STAT3 signaling pathway. J. Agric. Food Chem. 71 (30), 11454–11465. doi:10.1021/acs.jafc.3c01349
Sun, W. C., Guo, L., He, X. H., Zhu, Y. L., and Cao, S. R. (2025). Clinical efficacy of shenqi xiezhuo yin combined with haikun shenxi Capsules in the treatment of chronic kidney disease based on the “Clearing, Eliminating, and Tonifying” theory, 1-8. Chinese Journal of Clinical Research. Beijing, China: Chinese Association of Chinese Medicine. Available online at: https://link.cnki.net/urlid/11.5895.R.20251028.1532.004.
Tan, J. J. (2020). Study on the druggability of low molecular weight fucoidan for the treatment of nephrotic syndrome. Beijing, China: University of Chinese Academy of Sciences.
Tan, J., Wang, J., Geng, L., Yue, Y., Wu, N., and Zhang, Q. (2020). Comparative Study of fucoidan from Saccharina japonica and its depolymerized fragment on adriamycin-induced nephrotic syndrome in rats. Mar. Drugs 18 (3), 137. doi:10.3390/md18030137
Veena, C. K., Josephine, A., Preetha, S. P., and Varalakshmi, P. (2006a). Physico-chemical alterations of urine in experimental hyperoxaluria:a biochemical approach with fucoidan. J. Pharm. Pharmacol. 59 (3), 419–427. doi:10.1211/jpp.59.3.0012
Veena, C. K., Josephine, A., Preetha, S. P., Varalakshmi, P., and Sundarapandiyan, R. (2006b). Renal peroxidative changes mediated by oxalate:the protective role of fucoidan. Life Sci. 79 (19), 1789–1795. doi:10.1016/j.lfs.2006.06.014
Veena, C. K., Josephine, A., Preetha, S. P., Rajesh, N. G., and Varalakshmi, P. (2008). Mitochondrial dysfunction in an animal model of hyperoxaluria: a prophylactic approach with fucoidan. Eur. J. Pharmacol. 579 (1-3), 330–336. doi:10.1016/j.ejphar.2007.09.044
Wang, J. (2011). Wai Tai Mi Yao Fang (arcane essentials from the imperial library). Taiyuan: Shanxi Science and Technology Press.
Wang, X. M. (2014). Study on the mechanism of fucoidan from laminaria japonica against renal failure. Graduate University of Chinese Academy of Sciences (Institute of Oceanology, Chinese Academy of Sciences.
Wang, J., Wang, F., Yun, H., Zhang, H., and Zhang, Q. (2012). Effect and mechanism of fucoidan derivatives from laminaria japonica in experimental adenine-induced chronic kidney disease. J. Ethnopharmacol. 139 (3), 807–813. doi:10.1016/j.jep.2011.12.022
Wang, J., Liu, H., Li, N., Zhang, Q., and Zhang, H. (2014). The protective effect of fucoidan in rats with streptozotocin-induced diabetic nephropathy. Mar. Drugs 12 (6), 3292–3306. doi:10.3390/md12063292
Wang, Y., Nie, M., Lu, Y., Wang, R., Li, J., Yang, B., et al. (2015). Fucoidan exerts protective effects against diabetic nephropathy related to spontaneous diabetes through the NF-κB signaling pathway in vivo and in vitro. Int. J. Mol. Med. 35 (4), 1067–1073. doi:10.3892/ijmm.2015.2095
Wang, J., Zhang, Q., Li, S., Chen, Z., Tan, J., Yao, J., et al. (2020). Low molecular weight fucoidan alleviates diabetic nephropathy by binding fibronectin and inhibiting ECM-Receptor interaction in human renal mesangial cells. Int. J. Biol. Macromol. 150, 304–314. doi:10.1016/j.ijbiomac.2020.02.087
Wang, Y., Sun, Y., Shao, F., Zhang, B., Wang, Z., and Li, X. (2021). Low molecular weight fucoidan can inhibit the fibrosis of diabetic kidneys by regulating the kidney lipid metabolism. J. Diabetes Res. 2021, 7618166. doi:10.1155/2021/7618166
Wang, Y., Xue, P., Gao, L., Wang, X., Zhou, S., Wu, X., et al. (2025). Improved bioavailability of polydatin and its protective effect against cisplatin induced nephrotoxicity through self-assembled fucoidan and carboxymethyl chitosan delivery system. Int. J. Biol. Macromol. 287, 138577. doi:10.1016/j.ijbiomac.2024.138577
Wang, Z., Rong, X. L., Dai, C. X., Wang, Q., Lu, L. F., Zhang, W. T., et al. (2025). Fucoidan alleviates renal fibrosis in mice via akkermansia muciniphila-mediated suppression of NEU1-TLR4-NFκB signaling axis. Phytomedicine 145, 157060. doi:10.1016/j.phymed.2025.157060
Wong, K. G., Cheng, Y. F., Wu, V. H., Kiseleva, A. A., Li, J., Poleshko, A., et al. (2024). Growth factor-induced activation of MSK2 leads to phosphorylation of H3K9me2S10 and corresponding changes in gene expression. Sci. Adv. 10 (11), eadm9518. doi:10.1126/sciadv.adm9518
Xu, Y., Zhang, Q., Luo, D., Wang, J., and Duan, D. (2016). Low molecular weight fucoidan modulates P-selectin and alleviates diabetic nephropathy. Int. J. Biol. Macromol. 91, 233–240. doi:10.1016/j.ijbiomac.2016.05.081
Xu, J., Wang, Y., Wang, Z., Guo, L., and Li, X. (2021). Fucoidan mitigated diabetic nephropathy through the downregulation of PKC and modulation of NF-κB signaling pathway: in vitro and in vivo investigations. Phytother. Res. 35 (4), 2133–2144. doi:10.1002/ptr.6966
Xu, W., Ou, D., Zhao, Y., Liu, Y., Yan, P., Li, S., et al. (2025). Curcumin alleviates lipopolysaccharide-induced alveolar epithelial glycocalyx damage by modulating the Rac1/NF-κB/HPSE pathway. Cell. Signal 134, 111909. doi:10.1016/j.cellsig.2025.111909
Xue, M., Du, R., Zhou, Y., Liu, Y., Tian, Y., Xu, Y., et al. (2024). Fucoidan supplementation relieved kidney injury and modulated intestinal homeostasis in hyperuricemia mice. J. Agric. Food Chem. 72 (49), 27187–27202. doi:10.1021/acs.jafc.4c07209
Xue, T., Chen, X., Wang, J., Zhang, B., Sun, Y., Xin, J., et al. (2025). Laminaria japonica polysaccharide protects against liver and kidney injury in diabetes mellitus through the AhR/CD36 pathway. J. Food Sci. 90 (2), e70033. doi:10.1111/1750-3841.70033
Ying, J., Fang, H. J., Zhou, H. J., Huang, J., and Zhang, Y. L. (2023a). Efficacy of haikun shenxi capsules combined with benazepril in the treatment of chronic renal failure and its effects on renal function and oxidative stress indicators. Chin. Archives Traditional Chin. Med. 41 (10), 107–110. doi:10.13193/j.issn.1673-7717.2024.08.042
Ying, J., Zhang, C., Wang, Y., Liu, T., Yu, Z., Wang, K., et al. (2023b). Sulodexide improves vascular permeability via glycocalyx remodelling in endothelial cells during sepsis. Front. Immunol. 14, 1172892. doi:10.3389/fimmu.2023.1172892
Yu, Y. S. (2025). Therapeutic effect of niaoduqing combined with haikun shenxi on chronic renal insufficiency of spleen deficiency and dampness-turbidity type. Contemp. Med. Forum 23 (24), 132–134.
Yu, W. C., Huang, R. Y., and Chou, T. C. (2020). Oligo-fucoidan improves diabetes-induced renal fibrosis via activation of Sirt-1,GLP-1R,and Nrf2/HO-1:An in vitro and in vivo study. Nutrients 12 (10), 3068. doi:10.3390/nu12103068
Yuan, L., Cheng, S., Sol, W. M. P. J., van der Velden, A. I. M., Vink, H., Rabelink, T. J., et al. (2022). Heparan sulfate mimetic fucoidan restores the endothelial glycocalyx and protects against dysfunction induced by serum of COVID-19 patients in the intensive care unit. ERJ Open Res. 8 (2), 00652–02021. doi:10.1183/23120541.00652-2021
Yue, Q., Liu, Y., Li, F., Hong, T., Guo, S., Cai, M., et al. (2025). Antioxidant and anticancer properties of fucoidan isolated from Saccharina japonica brown algae. Sci. Rep. 15 (1), 8962. doi:10.1038/s41598-025-94312-7
Zahan, M. S., Hasan, A., Rahman, M. H., Meem, K. N., Moni, A., Hannan, M. A., et al. (2022). Protective effects of fucoidan against kidney diseases: pharmacological insights and future perspectives. Int. J. Biol. Macromol. 209 (Pt B), 2119–2129. doi:10.1016/j.ijbiomac.2022.04.192
Zha, X. Q., Lu, C. Q., Cui, S. H., Pan, L. H., Zhang, H. L., Wang, J. H., et al. (2015). Structural identification and immunostimulating activity of a laminaria japonica polysaccharide. Int. J. Biol. Macromol. 78, 429–438. doi:10.1016/j.ijbiomac.2015.04.047
Zhang, X. (2023). Clinical study of shenkang injection combined with haikun shenxi capsules in the treatment of chronic renal failure. Syst. Med. (11), 48–51. doi:10.19368/j.cnki.2096-1782.2023.11.048
Zhang, Y. K. (2024). Effects of haikun shenxi capsules combined with levocarnitine on renal function and inflammatory indicators in patients with chronic renal failure. Heilongjiang Med. J. 37 (04), 866–868. doi:10.14035/j.cnki.hljyy.2024.04.041
Zhang, Y. K. (2025). Effect of irbesartan combined with haikun shenxi capsules in the treatment of elderly patients with diabetic nephropathy. Chin. J. Med. Innovation 22 (07), 36–39.
Zhang, Q., Li, N., Zhao, T., Qi, H., Xu, Z., and Li, Z. (2005). Fucoidan inhibits the development of proteinuria in active heymann nephritis. Phytother. Res. 19 (1), 50–53. doi:10.1002/ptr.1623
Zhang, A. N., Wang, X. Y., Zhao, W., and Tang, X. F. (2025). Exploring the molecular mechanism of haikun shenxi capsules as adjuvant therapy for diabetic kidney disease through the interleukin-23/interleukin-17 inflammatory axis. J. Clin. Nephrol. 25 (06), 465–472.
Zhao, Z. J., Liang, K. F., Yang, M. J., and Zhang, X. X. (2007). Effects of haikun shenxi on expression of platelet-derived growth factor-B and mRNA in renal tissue of rats with adriamycin nephropathy. Zhongguo Zhong Yao Za Zhi 32 (20), 2156–2161. doi:10.16294/j.cnki.1007-659x.2007.06.027
Zhong, Z., Zhang, Y., Wei, Y., Li, X., Ren, L., Li, Y., et al. (2024). Fucoidan improves early stage diabetic nephropathy via the gut microbiota-mitochondria axis in high-fat diet-induced diabetic mice. J. Agric. Food Chem. 72 (17), 9755–9767. doi:10.1021/acs.jafc.3c08503
Zhu, J. J. (2023). Effect of haikun shenxi capsules combined with valsartan in the treatment of patients with chronic glomerulonephritis. Med. J. Chin. People's Health 35 (20), 112–114.
Keywords: charge barrier, chronic kidney disease, endothelial glycocalyx, fucoidan, glycosaminoglycan, heparan sulfate, proteinuria
Citation: Xin P, Ge C, Tang Y, He Y and Fu B (2026) Fucoidan as a renal protectant: mechanistic insights and therapeutic implications of endothelial glycocalyx targeting. Front. Pharmacol. 17:1749109. doi: 10.3389/fphar.2026.1749109
Received: 18 November 2025; Accepted: 07 January 2026;
Published: 16 January 2026.
Edited by:
Bernard Van Den Berg, Leiden University Medical Center (LUMC), NetherlandsReviewed by:
Irshad Ahamad, James Graham Brown Cancer Center, United StatesCopyright © 2026 Xin, Ge, Tang, He and Fu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Bin Fu, ZnViaW41MzkzQDEyNi5jb20=
†These authors have contributed equally to this work and share first authorship