bims-supasi 2026-07-12 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–07–12
twelve papers selected by
Jonathan Wolf Mueller, University of Birmingham

Reshaping the glycocalyx: the SULF extracellular endosulfatases as molecular editors of heparan Sulfate.
A glycosaminoglycan microarray identifies galectin-4 binding to sulfated glycosaminoglycans.
CRISPR activation screens identify core protein-dependent regulation of heparan sulfate sulfation and ligand specificity.
Controlled Synthesis of Sulfated Glycopolypeptides as Heparin Mimics via N-Carboxyanhydride ROP for Anticoagulant Property.
GPR17+ Oligodendrocyte Lineage Cells Regulate the Critical Period of Brain Development Through Novel Chondroitin Sulfate-Rich Structures.
Dehydroepiandrosterone Sulfate/Cortisol Ratio as a Biomarker of Depressive Symptoms in Late-Onset Hypogonadism: An Analysis of 3,005 Males.
Psychological distress, but not single-time endocrine stress markers, is associated with unexplained infertility: a prospective case-control study.
Sulfate starvation response modules connect sulfur metabolism to photorespiration and photosynthesis.
The primary nitrate response TGA1 and TGA4 transcription factors are negative regulators of sulfate uptake and metabolism.
Design and Engineering of an Artificial Bifunctional N-Deacetylase/N-Sulfotransferase for the Biosynthesis of N-Sulfated Heparosan.
Engineering gut microbiota-derived enzymes for glycosaminoglycan metabolism: Catalytic mechanisms, diversity, and technologies.
Sulfated polysaccharide from Gelidium crinale: modulation of angiogenesis and fibrosis in skin repair.

Biochem J. 2026 Aug 05. 483(8): 1437-1456

Reshaping the glycocalyx: the SULF extracellular endosulfatases as molecular editors of heparan Sulfate.

Rebecca-Joe Boustany, Sylvain D Vallet, Yara Awad, Evelyne Gout, Rebekka Wild, Romain R Vivès.

  Heparan sulfate proteoglycans are central modulators of cell-cell communication, largely through the information encoded in their sulfation patterns. Among extracellular regulators of this 'heparan sulfate code', the endosulfatases SULF1 and SULF2 have emerged as unique enzymes with the capacity to selectively remove 6-O-sulfate groups from heparan sulfate (HS) glucosamine residues. This activity distinguishes them from canonical lysosomal sulfatases and positions them as critical editors of HS from the extracellular matrix and cell-surface. Recent biochemical studies have highlighted their distinctive domain organization, extensive post-translational modifications, and finely tuned substrate specificity, revealing that 6-O-desulfation is a non-random, highly regulated process. Functionally, SULFs influence major signaling pathways and thereby participate in diverse biological processes, such as development, tissue homeostasis, injury repair, inflammation, and tumor progression. Accumulating evidence also implicates SULF1 and SULF2 in disease pathogenesis and highlights them as promising, yet underexplored, therapeutic targets. In the present review, we provide an updated perspective on SULF biology, emphasizing recent advances in functional characterization, their roles as extracellular 'code editors', and the therapeutic opportunities that may arise from targeting their activity. We also address several key questions that remain unresolved and that are needed to understand this complex mechanism of regulation.

Keywords:  glycosaminoglycans; heparan sulfate; molecular interactions; sulfatase

DOI:  https://doi.org/10.1042/BCJ20260351
Biochem Biophys Rep. 2026 Sep;47 102689

A glycosaminoglycan microarray identifies galectin-4 binding to sulfated glycosaminoglycans.

Kanae Sano, Meri Nagatomo, Katsunobu Shigematsu, Kazuhiko Yamasaki, Dinh Xuan Tuan Anh, Akira Shibuya, Yuya Otsuka, Toshikazu Minamisawa, Hiroaki Tateno.

Lectin-glycosaminoglycan (GAG) interactions remain incompletely understood despite their potential roles in cell signaling and immune regulation. In this study, we performed a comprehensive profiling of the binding specificity of 49 types of human endogenous lectins-including SIGLECs, C-type lectins, and galectins-for GAGs using GAG microarrays. GAGs containing 6-O-sulfation, such as heparin (HP), chondroitin sulfate C (CSC), and chondroitin sulfate E (CSE), exhibited broad binding to multiple SIGLECs and C-type lectins, whereas non-sulfated or low-sulfated GAGs exhibited minimal interactions, indicating a strong dependence on sulfation patterns. In contrast, most galectins displayed little or no detectable binding to GAG. Notably, galectin-4 (Gal-4) uniquely exhibited significant affinity for 6-O-sulfated GAGs, particularly HP. Surface plasmon resonance analysis revealed high-affinity binding of Gal-4 to HP (Kd = 4.70 × 10-8 M), substantially stronger than its carbohydrate recognition domains, indicating cooperative contributions of both N- and C-terminal CRDs of Gal-4. Molecular dynamics simulations further supported a binding mode involving both N- and C-terminal domains. Consistent with these findings, Gal-4 bound to endogenous HP-positive mast cells, and this interaction was competitively inhibited by HP. Together, these results identify Gal-4 as a unique galectin with a noncanonical capacity to recognize sulfated GAGs, revealing an alternative glycan-recognition mechanism beyond the conventional β-galactoside paradigm.

DOI: https://doi.org/10.1016/j.bbrep.2026.102689
bioRxiv. 2026 Jun 30. pii: 2026.06.29.735380. [Epub ahead of print]

CRISPR activation screens identify core protein-dependent regulation of heparan sulfate sulfation and ligand specificity.

Jack C Moore, Haruki Takeuchi, Caitlien Nguyen, Chin Huang, Digantkumar Chapla, Amrita Basu, Zhangjie Wang, Jian Liu, Kelley W Moremen, Ryan J Weiss.

Heparan sulfate proteoglycans (HSPGs) are essential cell surface and extracellular matrix glycoconjugates that mediate diverse biological processes through interactions between their heparan sulfate (HS) chains and extracellular ligands. While HS sulfation patterning is known to dictate ligand specificity, how cells control HS assembly to regulate these interactions remains incompletely understood. To systematically identify genetic modifiers of HS-protein interactions, we performed genome-wide CRISPR activation (CRISPRa) screens in HEK293T cells using binding of antithrombin (AT), which selectively recognizes 3- O -sulfated HS motifs, or the N -sulfation-specific antibody 10E4 as functional readouts. Strikingly, the screens revealed proteoglycan core proteins as key modulators of HS function. In particular, syndecan-1 (SDC1) emerged as a preferential enhancer of AT binding compared to other syndecan family members. Targeted upregulation of syndecan family members increased total HS levels, but only SDC1 enhanced AT binding. Structural and enzymatic analyses demonstrated that SDC1-associated HS chains contain elevated 6- O -sulfation and serve as superior substrates for 3- O -sulfotransferases relative to SDC2-associated HS chains. Additionally, SDC1 exhibited slower cell surface recovery, which was blocked by cycloheximide treatment, consistent with extended trafficking and biosynthetic processing. Overall, these findings indicate that proteoglycan core protein identity influences HS sulfation patterning and ligand-binding specificity and trafficking kinetics may contribute to core protein-dependent regulation of HS modification.

DOI: https://doi.org/10.64898/2026.06.29.735380
Biomacromolecules. 2026 Jul 06.

Controlled Synthesis of Sulfated Glycopolypeptides as Heparin Mimics via N-Carboxyanhydride ROP for Anticoagulant Property.

Abinash Padhy, Abhishek Shaw, Pallavi Kumari, Aritra Konar, Rounak Mukhopadhyay, Sujoy K Das, Sayam Sen Gupta.

Sulfated glycosaminoglycans (GAGs) play important roles in a number of physiological and pathophysiological processes, including the coagulation cascade, tumor growth inhibition, viral transmission, and antioxidation. Heparin, a naturally occurring, highly sulfated GAG, remains widely used as a clinical anticoagulant. However, risks of contamination, variable pharmacological response, and its adverse side effects have motivated the development of synthetic alternatives. Earlier reports of heparin-mimicking polymers have focused on either incorporating sulfate groups via postpolymerization methods or polymerizing free sulfonic acid-containing monomers via RAFT and ROMP. Synthesis using more sensitive polymerization techniques such as ATRP, NMP, and NCA-ROP, which require polymerization of protected sulfate-containing monomers, remains challenging and largely unexplored. Herein, we report a novel synthetic methodology to prepare mannose-6-sulfate (M6S)-based glycopolypeptides as a structural mimic of heparin. Initially, the protected sulfate group was introduced, particularly at the 6-position of mannose, and an M6S-based N-carboxyanhydride (NCA) monomer was prepared. Further, the protected glycopolypeptides were synthesized via NCA-ROP techniques. The fully water-soluble sulfated M6S glycopolypeptides, subsequently obtained after deprotection steps, exhibited minimal cytotoxicity toward mammalian cells and negligible hemolytic activity, underscoring their potential suitability for biomedical applications. Furthermore, both aPTT and PT assays indicate that these synthetic materials can act as anticoagulants by significantly prolonging clotting times with performance comparable to that of heparin. The control mannose glycopolypeptides exhibited no activity, demonstrating the importance of sulfate groups in achieving anticoagulation. The mechanistic investigations elucidated the anticoagulation pathway to be dependent on factors IIa and Xa. This methodology of developing sulfated glycopolypeptides might bring in more valuable therapeutics for antiviral or anticancer materials.

DOI: https://doi.org/10.1021/acs.biomac.6c00475
Glia. 2026 Sep;74(9): e70188

GPR17+ Oligodendrocyte Lineage Cells Regulate the Critical Period of Brain Development Through Novel Chondroitin Sulfate-Rich Structures.

Takahiro Tanaka, Aurelien Kerever, Yuji Suzuki, Taro Kunitomi, Kana Kato, Yuri Yamashita, Kyohei Higashi, Chihiro Akazawa, Fumihito Saitow, Hidenori Suzuki, Eri Arikawa-Hirasawa.

  The extracellular matrix (ECM) of the brain undergoes dynamic remodeling during development and is crucial for neuronal plasticity. While chondroitin sulfates (CS) regulate oligodendrocyte differentiation and myelination, their relationship with oligodendrocyte precursors (OPCs) and synaptic plasticity remains unclear. This study investigated a novel CS-rich ECM structure, its origin, and its role in synaptic plasticity. Using immunohistochemistry, disaccharide analysis, and dendritic spine characterization in mice, we examined postnatal development and analyzed single-cell RNA (scRNA) sequencing data from the National Center for Biotechnology Information database. We identified patch-like structures labeled with the chondroitin sulfate 56 (CS56) antibody (CS clusters) distinct from Wisteria floribunda agglutinin-positive perineuronal nets. Oligodendrocyte lineage cells expressing G protein-coupled receptor 17 (GPR17) localized at CS cluster centers, emerging postnatally and peaking at day 14, preceded CS cluster formation. ScRNA sequencing of Gpr17+ cells revealed the expression of carbohydrate sulfotransferase 3 (Chst3) and uronyl 2-sulfotransferase (Ust), genes coding enzymes synthesizing type C and D CS disaccharides, the primary components of the CS56 antibody epitope. Disaccharide analysis revealed elevated levels of type D chondroitin sulfate at day 35. Notably, dendritic spines within the CS clusters were longer and larger than those outside these regions, suggesting enhanced synaptic connectivity. Our findings reveal a CS-rich structure in the brain ECM that is causally linked to GPR17+ oligodendrocyte lineage cells and closely related to neuronal circuit development. The morphological differences in dendritic spines within CS clusters and persistence of GPR17+ oligodendrocyte lineage cells beyond the postnatal period suggest additional functions that warrant further investigation.

Keywords:  chondroitin sulfate chains; dendritic spine plasticity; extracellular matrix; glycosaminoglycan; neurodevelopment; oligodendrocytes; resident immature oligodendrocytes

DOI:  https://doi.org/10.1002/glia.70188
World J Mens Health. 2026 Jun 09.

Dehydroepiandrosterone Sulfate/Cortisol Ratio as a Biomarker of Depressive Symptoms in Late-Onset Hypogonadism: An Analysis of 3,005 Males.

Haruhiko Wakita, Riho Kasai, Yukiko Ota, Takashi Kanda, Yuta Anno, Keisuke Ishikawa, Ayumu Taniguchi, Yuka Uesaka, Taiji Nozaki, Masato Shirai, Kazuhiro Kobayashi, Akira Tsujimura.

   PURPOSE: Depressive symptoms related to late-onset hypogonadism (LOH) have attracted attention due to their impact on absenteeism and presenteeism. Although LOH symptoms are not consistently associated with serum testosterone levels, elevated cortisol and decreased dehydroepiandrosterone sulfate (DHEA-S) are frequently observed in depressed individuals, suggesting their potential as biomarkers. We investigated the relationship between depressive symptoms and the DHEA-S/cortisol (D/C) ratio in a large cohort of males with LOH symptoms.
MATERIALS AND METHODS: We retrospectively analyzed data from 3,005 males with LOH symptoms who visited our hospital or affiliates between May 2016 and March 2024. Symptoms were assessed using the Aging Male Symptoms (AMS) scale, Sexual Health Inventory for Men, International Prostate Symptom Score, and Beck Depression Inventory (BDI). Endpoints included correlations between serum testosterone and D/C ratio, associations between the D/C ratio and AMS and BDI scores, and multivariable-adjusted relationships between the D/C ratio and symptom scores.
RESULTS: The mean age was 47.5±12.3 years, mean serum testosterone of 5.4±2.4 ng/mL and mean D/C ratio of 33.8±29.2. No significant correlation was observed between testosterone and D/C ratio (p=0.368). In contrast, the D/C ratio showed significant negative correlations with AMS (r=-0.058, p=0.001) and BDI (r=-0.085, p<0.001) scores. Trend analysis demonstrated a decline in the D/C ratio with increasing AMS and BDI severity (p for trend<0.001). Testosterone showed no association with AMS or BDI scores. After adjusting for age, aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, total cholesterol, triglyceride, hemoglobin A1c, only the BDI score remained associated with the D/C ratio (β=-0.054, p=0.002).
CONCLUSIONS: The D/C ratio demonstrates a significant association with depressive symptoms and may serve as a potential biomarker. Its assessment may improve psychological evaluations and management in this population.

Keywords:  Biomarkers; Dehydroepiandrosterone sulfate; Depression; Hydrocortisone; Hypogonadism

DOI:  https://doi.org/10.5534/wjmh.250393
Front Endocrinol (Lausanne). 2026 ;17 1859428

Psychological distress, but not single-time endocrine stress markers, is associated with unexplained infertility: a prospective case-control study.

Sertaç Ayçiçek, Berçem Ayçiçek.

   Background: Psychological distress is common among women with unexplained infertility and may interact with neuroendocrine stress pathways. However, the relevance of single-time endocrine stress markers such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in reflecting chronic emotional burden remains uncertain.
Objective: To investigate the association between psychological distress and single-time endocrine stress markers in women with unexplained infertility and to compare psychometric assessment with synchronized hormonal measurements.
Methods: In this prospective case-control study, consecutive women with primary unexplained infertility (n = 50) and age-matched fertile controls (n = 52) were enrolled from the same tertiary gynecology outpatient clinic. Psychological distress was assessed using the Hospital Anxiety and Depression Scale (HADS). Clinically relevant psychological distress was defined as HADS-Anxiety ≥8 and/or HADS-Depression ≥8. Serum cortisol and DHEAS concentrations were measured under standardized morning fasting conditions during the early follicular phase. Multivariable logistic regression analysis was performed using a parsimonious adjusted model including age, body mass index, smoking status, residential environment, cortisol level, and HADS-defined psychological distress.
Results: Women with unexplained infertility demonstrated significantly higher HADS-Anxiety and HADS-Depression scores compared with fertile controls (p < 0.05 for both comparisons). Based on predefined HADS subscale cut-off values (HADS-A ≥8 and/or HADS-D ≥8), HADS-defined psychological distress was significantly more prevalent in the unexplained infertility group (76.0% vs. 42.3%, p = 0.001). Although follicle-stimulating hormone and estradiol levels differed significantly between groups, all measured values remained within physiological reference ranges. No statistically significant between-group differences were observed for cortisol, dehydroepiandrosterone sulfate (DHEAS), or anti-Müllerian hormone levels. In the final parsimonious multivariable logistic regression model adjusted for age, body mass index, smoking status, residential environment, cortisol level, and HADS-defined psychological distress, psychological distress remained independently associated with unexplained infertility (adjusted OR 3.907, 95% CI 1.610-9.478, p = 0.003). Exploratory ROC analyses demonstrated limited discriminatory performance of isolated single-time cortisol and DHEAS measurements for identifying HADS-defined psychological distress.
Conclusion: Psychological distress was more prevalent among women with unexplained infertility, whereas single-time serum endocrine stress markers were not significantly different between groups. These findings support the relevance of psychological assessment in women with unexplained infertility; however, the cross-sectional case-control design does not allow causal inference regarding the direction of this association.

Keywords:  DHEAS; HADS; Neuroendocrinology; Unexplained infertility; cortisol; psychological distress

DOI:  https://doi.org/10.3389/fendo.2026.1859428
Plant J. 2026 Jul;127(1): e71019

Sulfate starvation response modules connect sulfur metabolism to photorespiration and photosynthesis.

Suvajit Basu, Inken Thiemann, Stefan Timm, Varsa Shukla, Philipp Baessler, Philipp Westhoff, Stanislav Kopriva, Daniela Ristova.

  Mineral nutrients are essential for plant growth and development. Sulfur (S), as a macronutrient, is incorporated into numerous critical S-containing metabolites that play key roles in mitigating both abiotic and biotic stresses. Understanding how plants regulate S homeostasis and integrate it with other physiological processes is crucial for developing crops that can better withstand environmental challenges. Here, we demonstrate that the conserved sulfate starvation transcriptional response across Arabidopsis, tomato, rice, and Setaria is limited to only seven genes. We further characterize the roles of two of these genes, PYD4 (PYRIMIDINE 4) and MGL (METHIONINE GAMMA-LYASE), in S metabolite regulation and the sulfate starvation response. Our genetic and biochemical analyses show that PYD4 is embedded within the S starvation network, positively regulating transcript levels of key S-marker genes, including four of the seven conserved genes across these species, and serving as an integrator of S metabolism and photorespiration. MGL also positively regulates S-marker genes, while additionally modulating diverse processes under sulfate starvation, such as photosynthesis and oxidoreductase homeostasis. Notably, MGL-deficient lines fail to respond adequately to sulfate starvation and exhibit impaired mechanisms for maintaining photosynthetic efficiency. Overall, our findings indicate that the S starvation response is deeply embedded within primary plant metabolism. Disruption of its regulators alters metabolism at multiple levels, affecting traits central to crop improvement, such as photorespiration and photosynthesis.

Keywords:  photorespiration; photosynthesis; starvation; sulfate; transcription

DOI:  https://doi.org/10.1111/tpj.71019
Plant Physiol. 2026 Jul 06. pii: kiag444. [Epub ahead of print]

The primary nitrate response TGA1 and TGA4 transcription factors are negative regulators of sulfate uptake and metabolism.

Suvajit Basu, Varsa Shukla, Ira Trivedi, Pengxin Yu, Hanna Bechtel, Anna Koprivova, Agnieszka Sirko, Anna Wawrzyńska, Daniela Ristova.

Although the synergistic effects of nitrogen (N) and sulfur (S) on crop performance are well established, the regulatory network integrating these pathways remains largely unknown. Clade I TGA transcription factors, TGA1 and TGA4, function within the second and third layers of the primary nitrate-responsive transcriptional cascade and are also implicated in immunity. Here we show that provision of nitrate rapidly induces sulfate uptake and assimilation through a yet undefined mechanism, followed by a delayed repression of SULTR1;2 mediated by clade I TGA transcription factors. In contrast, clade II TGAs and the nitrate signaling components NRT1.1 and NLP7 were not involved in this regulation. The binding analysis showed that both TGA1 and TGA4 bind to the promoter of high-affinity sulfate transporter, SULTR1;2, while in vivo assay confirmed that TGA1 and TGA4 repress the activity of AtSULTR1;1 and AtSULTR1;2 promoters. Genetic and biochemical analysis further revealed that clade I TGA TFs negatively regulate sulfur metabolism not only under nitrate provision, but also under sulfate starvation. Accordingly, the tga1 tga4 double mutant displayed enhanced sulfate uptake, increased cysteine accumulation, and improved fitness under long-term sulfate limitation. Additionally, TGA1 and TGA4 influenced sulfur-containing secondary metabolism, including indolic glucosinolates and camalexin during biotic stress. By coordinating sulfate acquisition with nitrogen signaling, clade I TGAs contribute to maintaining nutrient homeostasis and plant performance. This work advances our understanding of mineral nutrient integration in plants and provides new perspectives for improving nutrient use efficiency and stress resilience in crops.

DOI: https://doi.org/10.1093/plphys/kiag444
Adv Sci (Weinh). 2026 Jul 10. e76499

Design and Engineering of an Artificial Bifunctional N-Deacetylase/N-Sulfotransferase for the Biosynthesis of N-Sulfated Heparosan.

Xintong Xi, Ruirui Xu, Daoan Wang, Guobin Yin, Xinjing Wang, Haiqin Chen, Guocheng Du, Jian Chen, Zhen Kang.

  Heparin is a widely used anticoagulant, while its traditional animal-derived production faces significant challenges in safety and scalability. The active expression of the initiating-step bifunctional enzyme N-deacetylase/N-sulfotransferase (NDST) in bacteria remains a key bottleneck in heparin biosynthesis. Here, we firstly mined and characterized diverse polysaccharide N-deacetylases (NDases) in Escherichia coli and revealed several NDases that are active toward the deacetylation of heparosan. An artificial NDDr-RL-ST was designed and constructed by fusing an active NDase with a heterogenous NST domain. The NDDr -MEc/ST variant with a 7.48-fold improvement in catalytic efficiency was engineered by combining dynamic cross-correlation analysis, sequence consensus analysis, and mutation-effect prediction with sequential linker optimization and rational mutagenesis, resulting in enhanced substrate binding, active-site stabilization, and improved inter-domain coordination. NDDr -MEc/ST efficiently converted heparosan to N-sulfated polysaccharide with a sulfation degree of 82.8%. The results highlighted the critical role of N-sulfotransferase interaction with NDDr domain in stabilizing the catalytic conformation essential for bifunctional enzyme activity. Moreover, this work also provided valuable insights for the rational design of artificial multifunctional enzymes for polysaccharide modification.

Keywords:  Escherichia coli; N‐deacetylase/N‐sulfotransferase; N‐sulfated heparosan; artificial bifunctional enzyme; heparin; polysaccharide

DOI:  https://doi.org/10.1002/advs.76499
Biotechnol Adv. 2026 Jul 07. pii: S0734-9750(26)00184-9. [Epub ahead of print]92 108978

Engineering gut microbiota-derived enzymes for glycosaminoglycan metabolism: Catalytic mechanisms, diversity, and technologies.

Jiahuan Dong, Yanhua Cui, Xiaojun Qu.

  Glycosaminoglycans (GAGs) are structurally complex, sulfate-containing polysaccharides that are abundant in animal-derived foods and host tissues, and they are associated with diverse physiological activities. Their gastrointestinal digestion and utilization depend largely on the enzymatic repertoire of the gut microbiota, which has stimulated growing interest in the mechanisms underlying microbial GAG metabolism. In this context, enzyme engineering is expanding the analytical and biotechnological applications of these enzymes, ranging from GAG disaccharide composition analysis to the preparation of therapeutic GAG-derived oligosaccharides. This review focuses on two key enzymes that govern gut microbial GAG metabolism, polysaccharide lyases (PLs) and sulfatases. We summarize their catalytic mechanisms, substrate specificities, and roles in metabolic pathways. Particular attention is given to structural and functional variations within PL families and S1 sulfatase subfamilies identified in gut microbiota. Recent studies have increasingly revealed enzymes with substrate-specific catalytic properties and gut-adapted functionalities, which in turn provide a mechanistic basis for their rational engineering and targeted design. Overall, these findings underscore the importance of systematic enzymology informing enzyme-engineering strategies and provide new avenues for the selective transformation of dietary sulfated glycans and for the biotechnological production of functional oligosaccharides.

Keywords:  Catalytic mechanisms; Enzyme engineering; Glycosaminoglycans (GAGs); Gut microbiota; Polysaccharide lyases (PLs); Sulfatases

DOI:  https://doi.org/10.1016/j.biotechadv.2026.108978
NPJ Sci Food. 2026 Jul 04.

Sulfated polysaccharide from Gelidium crinale: modulation of angiogenesis and fibrosis in skin repair.

Yi Liu, Haiyan Zheng, Yizhu Chen, Bomi Ryu, Zhong-Ji Qian.

Scar tissue formation is a common pathological outcome of skin repair after injury, characterized by excessive collagen deposition and closely associated with inflammation and angiogenesis. This study investigated the effects and related signaling changes of a food-derived sulfated polysaccharide from the red alga Gelidium crinale (GNP) on angiogenesis and scar formation using in vitro and in vivo models. Human umbilical vein endothelial cells (HUVECs) and human keloid fibroblasts (HKFs) were used to evaluate the biological activity of GNP, while an OSA-CMCS self-crosslinking hydrogel was employed as a delivery vehicle to improve local administration in a mouse wound-healing model. GNP significantly inhibited HUVEC migration, invasion, and tube formation, accompanied by reduced expression of angiogenesis-related factors, including PDGF, ANG-II, and HIF-1α, suggesting impaired angiogenic activation. In HKFs, GNP decreased TGF-β1 expression and modulated downstream fibrosis-related signaling, thereby suppressing collagen and fibronectin production. Moreover, incorporation of GNP into the OSA-CMCS hydrogel reduced inflammatory responses, angiogenesis, and collagen deposition in vivo. These findings demonstrate the potential of GNP as a natural anti-scar candidate and provide a promising strategy for the high-value utilization of Gelidium crinale polysaccharides.

DOI: https://doi.org/10.1038/s41538-026-00977-3