bims-supasi 2026-05-24 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–05–24
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Human Sulfatases Use Dual Mechanisms to Control Growth Factor-Heparan Sulfate Interactions.
Heparan sulfate promotes autoactivation of procathepsin K by destabilizing the propeptide-catalytic domain interaction.
Characterization of dermatan sulfate and chondroitin sulfate profiles during brain regeneration in Styela plicata.
Structural insights into tyrosine sulfation of CCR5 by human tyrosylprotein sulfotransferase-1.
Unveiling and suppressing side reactions in the deacetylation and deaminative depolymerization of fucosylated chondroitin sulfate for enhanced oligosaccharide preparation.
Antiviral Activity of Dendritic Heparan Sulfate Mimetics against Respiratory Syncytial Virus and Herpes Simplex Virus‑1.
Plasma Heparan Sulfate Structural Variation and Phenotypic Heterogeneity in Pediatric Acute Respiratory Distress Syndrome.
Kinetic Overview of Polynuclear Platinum(II) Complexes in Heparan Sulfate Substitution: Mimetic Model Analysis and Mechanistic Perspectives.
Chondroitin sulfate-functionalized GSH-responsive lipid-nanoparticle inhibits melanoma metastasis through suppressing STAT3 activation.
Exploring the nutritional and bioactive potential of microalgal sulfated polysaccharides for functional food applications.
Impact of sulfate groups on the physicochemical properties of Fucoidan from Lessonia trabeculata.
Sulfate handling in proximal renal tubular defects: an exploratory study.
pH-responsive, self-lubricating hyaluronic acid-chondroitin sulfate-chitosan hydrogel for articular cartilage repair.
Oxysterol undersulfation promotes osteoarthritis by fueling chondrocyte lipid accumulation.

ACS Chem Biol. 2026 May 18.

Human Sulfatases Use Dual Mechanisms to Control Growth Factor-Heparan Sulfate Interactions.

Bryce M Timm, Julianna L Follmar, Ryan N Porell, Sylvain D Vallet, Kimberly Glass, Bryan E Thacker, Charles A Glass, Philip Gordts, Romain R Vivès, Kamil Godula.

Growth factor signaling governs essential cellular processes, and its precision relies on interactions with heparan sulfate on the cell surface. The sulfation pattern of heparan sulfate dictates its capacity to bind specific growth factors and their receptors, thereby controlling the signaling strength and specificity. Extracellular endosulfatases, including sulfatase 1 and sulfatase 2, further modulate these interactions by selectively removing sulfate groups from defined regions of heparan sulfate. Although these enzymes are known to influence developmental- and disease-related signaling, their direct effects on growth factor recognition have remained unclear. Using a panel of bioengineered heparan sulfate conjugates with defined sulfation compositions, this study examines how the structural features of heparan sulfate govern its regulation by the sulfatases. By tracking enzyme binding and catalytic remodeling, we found that both enzymes rely on two coordinated mechanisms: catalytic desulfation of heparan sulfate and competitive binding that transiently prevents growth factor association. The balance between catalytic remodeling and competitive binding depends on the sulfation characteristics of the heparan sulfate substrate and the identity of the growth factor and differs between the two enzyme isoforms. These findings provide a new framework for understanding how extracellular sulfatases shape growth factor signaling in both development and disease.

DOI: https://doi.org/10.1021/acschembio.6c00368
Biochem J. 2026 Jun 03. 483(6): 967-980

Heparan sulfate promotes autoactivation of procathepsin K by destabilizing the propeptide-catalytic domain interaction.

Huanmeng Hao, Xiaoxiao Zhang, Jian Liu, Ding Xu.

  Procathepsin K (pro-CtsK) is the zymogen of cathepsin K (CtsK), a collagenase that is essential for bone resorption. Pro-CtsK is known to bind heparan sulfate (HS), but the biological significance of the interaction remains unclear. Here, we report that HS accelerates the autoprocessing of pro-CtsK in a manner dependent on both sulfation pattern and oligosaccharide length. We discovered a previously unknown electrostatic interaction between the propeptide and the catalytic domain, which stabilizes the conformation of the propeptide and prevents it from intermolecular proteolytic activation. HS accelerates autoprocessing of pro-CtsK by disrupting this critical electrostatic interaction. Mechanistically, HS competes with two glutamic acids in the propeptide for binding to three basic residues on the catalytic domain, thereby substantially altering the conformation of the propeptide and making it more labile for autoprocessing. We further discovered that HS is highly enriched in secretory lysosomes of osteoclasts and might be directly involved in autoactivation of CtsK.

Keywords:  Protease; cathepsin; glycosaminoglyan; lysosome; osteoclasts

DOI:  https://doi.org/10.1042/BCJ20260109
FEBS J. 2026 May 21.

Characterization of dermatan sulfate and chondroitin sulfate profiles during brain regeneration in Styela plicata.

Taynan Motta Portal, Samara de Oliveira Pimentel, Bruno da Costa Rodrigues, Mauro Sérgio Gonçalves Pavão, Rodrigo Nunes da Fonseca, Cintia Monteiro de Barros.

  Neuroregeneration is the ability of nervous tissue to renew itself after injury. This process is highly limited in mammals. In contrast, marine chordates such as ascidians display a remarkable regenerative capacity, making them valuable models to understand neural regeneration. This study investigated dermatan sulfate (DS) and chondroitin sulfate (CS) profiles during brain regeneration in the ascidian Styela plicata. Neurodegeneration was induced by 3-acetylpyridine (3-AP), after which neural complex (NC) analyses were conducted using histology, RT-qPCR, liquid chromatography, behavioral testing, and phylogenetic methods at 1,5 and 10-day postinjection. One day after treatment, the cerebral ganglion exhibited significant degeneration, followed by morphological and molecular recovery at 10 days, when neuronal and synaptic markers returned to control levels. Gene expression analyses revealed early upregulation of C-6, C-4, and C-2 sulfotransferases in the final stage. For the first time, the presence of dermatan 2,6 sulfate (D2,6S) and chondroitin 4 sulfate (C4S) in the cortex of the cerebral ganglion was described and 2,6 sulfate disaccharides were found to make up the majority of the NC, emphasizing their relationship with regeneration. A behavioral test revealed that co-injecting 3-AP and D2,6S restored the compromised siphon movements. Finally, ascidian DS epimerase (DSE) was most closely related to vertebrate DSE type 2, which is found in the brains of mammals. Together, these results indicate that specific glycosaminoglycan sulfation patterns are dynamically regulated during neural regeneration in ascidians. This study provides new insights into the molecules and strategies promoting neuroregeneration in vertebrates and advances the field of regenerative medicine.

Keywords:  carbohydrate sulfotransferase; dermatan sulfate epimerase; glycosaminoglycans; neuroregeneration; tunicate

DOI:  https://doi.org/10.1111/febs.70598
FEBS J. 2026 May 22.

Structural insights into tyrosine sulfation of CCR5 by human tyrosylprotein sulfotransferase-1.

Shinnosuke Tanaka, Hirai Asano, Kota Toyoda, Toshiaki Nishiyori, Hidetaka Kojo, Kazuto Kiyomatsu, Katsuhisa Kurogi, Yoichi Sakakibara, Etsuko Nishimoto, Takamasa Teramoto, Yoshimitsu Kakuta.

  Post-translational sulfation of the chemokine receptor CCR5 is involved in crucial biological processes such as viral infection and chemokine signaling. This sulfation can occur at the N-terminal tyrosine residues (Y3, Y10, Y14, and Y15) of CCR5 and is catalyzed by human tyrosylprotein sulfotransferases (hTPSTs) within the Golgi lumen. However, the detailed molecular mechanism by which these tyrosine residues are sulfated remains unresolved. To elucidate the mechanism, we determined the crystal structure of a soluble domain of hTPST1 bound to the sulfate donor product 3'-phosphoadenosine 5'-phosphate (PAP) and a modified 18-residue CCR5 peptide designed to isolate the Y3-centered binding mode, at 3.2 Å resolution, with six peptide residues ordered. This structure defines key interactions consistent with Y3 sulfation and is consistent with previous biochemical data. Based on the crystal structure and prior knowledge, we constructed peptide docking models for Y10, Y14, and Y15 sulfation, as well as full-length hTPST1-PAP-CCR5 docking models. The crystal structure provides experimental insight into Y3 recognition, whereas the docking models provide testable hypotheses for how the other sulfation sites may be accommodated in the context of CCR5.

Keywords:  CCR5; crystal structure; structural modeling; tyrosine sulfation; tyrosylprotein sulfotransferase

DOI:  https://doi.org/10.1111/febs.70597
Carbohydr Polym. 2026 Aug 01. pii: S0144-8617(26)00519-9. [Epub ahead of print]385 125402

Unveiling and suppressing side reactions in the deacetylation and deaminative depolymerization of fucosylated chondroitin sulfate for enhanced oligosaccharide preparation.

Shengtao Yang, Ying Pan, Wenwen Ma, Hao Zeng, Na Gao, Wenwu Sun, Ronghua Yin, Jinhua Zhao.

  Deacetylative-deaminative depolymerization represents a critical methodology for selective glycosidic bond cleavage in glycosaminoglycans, essential for structural elucidation and bioactive oligosaccharide preparation. While concurrent side reactions in fucosylated chondroitin sulfate (FCS) during this process remain poorly understood. Using highly regular FCS from Stichopus horrens as a model, side reactions during hydrazinolysis and deamination cleavage were systematically characterized. We report the first discovery that backbone glycosidic bond scission-preferentially at β1,3-linkages-dominates the de-N-acetylation step, with both deacetylation and this side reaction following first-order kinetics. Notably, GlcA residues at newly exposed reducing ends may undergo unique reductive-isomerization under hydrazinolysis condition. Orthogonal design optimization achieved 1.9-fold higher efficiency in generating deacetylated units versus conventional methods. Additionally, nitrite-mediated "peeling-off" was identified as the critical side reaction during deaminative cleavage, wherein residual nitrous acid species "peel" the target oligosaccharides. Scavenger screening demonstrated that immediate introduction of l-ascorbic acid, ammonium salts, or organic amines effectively quenches this side reaction, eliminating by-products and enhancing reproducibility. This study clarifies the key side reactions during the deacetylation-deaminative depolymerization of FCS, laying the methodological foundation for precise structural analysis of FCS and development of FCS-based therapeutics.

Keywords:  Deacetylation; Deaminative Depolymerization; Fucosylated chondroitin sulfate; Glycosaminoglycan; Oligosaccharide; Side reaction

DOI:  https://doi.org/10.1016/j.carbpol.2026.125402
ACS Omega. 2026 May 12. 11(18): 26533-26543

Antiviral Activity of Dendritic Heparan Sulfate Mimetics against Respiratory Syncytial Virus and Herpes Simplex Virus‑1.

Yiming Yue, Amelia Chang, Sam Spijkers-Shaw, Rory Devlin, Ye Li, Phillip M Rendle, Ashley Nutsford, Blake Sullivan-Hill, Carol Wang, Olga V Zubkova, Natalie E Netzler, John A Taylor.

Heparan sulfate (HS) can act as an attachment receptor for many different animal viruses. Virus binding to HS occurs through electrostatic interactions between the negatively charged sulfate and carboxyl groups of HS and positively charged amino acids present in viral proteins. Soluble heparin, a glycosaminoglycan related to HS, can inhibit infection by many viruses, but the clinical use of heparin is limited by its anticoagulant activity. Synthetic HS mimetics that lack anticoagulant activity have been developed and can inhibit virus infection in vitro and in vivo. Building on this precedent, we investigated inhibition of respiratory syncytial virus (RSV) and herpes simplex virus type-1 (HSV-1) by a set of tri- and tetrameric dendritic HS mimetics. Several of these compounds exhibited submicromolar inhibition of both viruses when used as receptor decoys in assays of virus entry, and a lead compound inhibited the cell-to-cell spread of RSV in vitro and RSV-mediated membrane fusion. Additionally, we observed synergistic effects when an HS mimetic was used in combination with clinical antiviral remdesivir. The solubility, lack of anticoagulant activity, and antiviral potency of these dendritic HS mimetics make them a promising new class of broad-spectrum antiviral therapeutics.

DOI: https://doi.org/10.1021/acsomega.5c12846
Res Sq. 2026 May 04. pii: rs.3.rs-9337695. [Epub ahead of print]

Plasma Heparan Sulfate Structural Variation and Phenotypic Heterogeneity in Pediatric Acute Respiratory Distress Syndrome.

Colin J Sallee, Aline B Maddux, Joseph A Hippensteel, Daniela Markovic, Zhangjie Wang, Jian Liu, Kaori Oshima, Robert P Richter, Andreas Schwingshackl, Peter M Mourani, David Elashoff, Eric P Schmidt, Anil Sapru.

Endothelial glycocalyx (eGCX) shedding contributes to microvascular endotheliopathy in Acute Respiratory Distress Syndrome (ARDS) and is a potential underrecognized source of phenotypic heterogeneity. In pediatric ARDS (PARDS), we examined whether circulating heparan sulfate (HS) signatures, as readouts of eGCX shedding, capture inter-individual variability beyond other eGCX components and protein biomarkers, whether specific HS structural features are enriched, and whether they correlate with heparanase-1 (HPSE) activity. We retrospectively analyzed plasma samples (2018-2020) from children with and without PARDS. Mass spectrometry quantified glycosaminoglycans and sulfation subtypes alongside HPSE activity, while protein biomarkers were measured by multiplex assay. Among 46 children (36 PARDS, 10 no PARDS), principal component analysis identified three components explaining 63% of variance. The primary component (PC1) was driven by 6- O - and N -sulfated HS subtypes, while a secondary component (PC2) reflected inflammatory proteins. In PARDS, higher PC1 scores were associated with worse organ dysfunction and fewer ventilator-free days. Higher total HS levels were associated with enrichment of sulfated HS (including 6- O - and N -sulfated subtypes), whereas the opposite pattern was observed in non-PARDS; higher HPSE activity further correlated with these subtypes. These preliminary findings suggest that variation in circulating HS signatures identifies a distinct endothelial-derived biological axis linked to clinical outcomes.

DOI: https://doi.org/10.21203/rs.3.rs-9337695/v1
ACS Omega. 2026 May 12. 11(18): 26779-26796

Kinetic Overview of Polynuclear Platinum(II) Complexes in Heparan Sulfate Substitution: Mimetic Model Analysis and Mechanistic Perspectives.

Frederico Henrique do C R Ferreira, Nicholas P Farrell, Luiz Antônio S Costa.

Polynuclear platinum-(II) complexes (PPCs) represent a promising class of anticancer agents, offering enhanced efficacy and reduced toxicity compared with traditional mononuclear platinum drugs. Their interactions extend beyond DNA to include noncovalent and covalent binding with biologically relevant anions, such as sulfates and carboxylates, in glycosaminoglycans (GAGs) like heparan sulfate (HS) and chondroitin sulfate. This study investigates the chloride substitution mechanisms in PPCs using a Cl-PtN3 model, evaluating both aquation-driven and direct substitution pathways with GAG mimetic models of iduronic acid, IdoA-(2S), and glucose, GlcNS-(6S). A computational benchmarking analysis identified the double-hybrid DFT functional B2PLYP as the most accurate method, displaying an absolute deviation of only 1.05 kcal mol-1 from the DLPNO-CCSD-(T) reference. Free energy profiles revealed similar energy transition-state species ranging from ca. 26 to 30 kcal mol-1, while direct substitutions exhibit lower activation barriers but are thermodynamically less favorable. The inclusion of explicit water molecules in the solvation layer was also addressed and significantly drove the results toward experimental data, with a better description of the active complex. These findings, added to our microkinetic analysis, provide insight into PPC ligand-exchange mechanisms, contributing to the rational design of next-generation platinum-based anticancer therapeutics.

DOI: https://doi.org/10.1021/acsomega.5c13472
Int J Pharm. 2026 May 15. pii: S0378-5173(26)00437-0. [Epub ahead of print]699 126989

Chondroitin sulfate-functionalized GSH-responsive lipid-nanoparticle inhibits melanoma metastasis through suppressing STAT3 activation.

Yawen Yao, Min Zhang, Sai Xu, Guoping Wu, Xinwang Meng, Juan Li, Hua Yu.

  Tumor metastasis results in high mortality rate in patients with advanced melanoma. The hyperphosphorylation of signal transducer and activator oftranscription3 (STAT3) is closely associated with the proliferation and metastasis of melanoma. Here, we proposed a lipid-nanoparticle (CSD@DNLP) derived from the chondroitin sulfate (CS)-conjugated deoxycholic acid (DOCA) polymer (CS-ss-DOCA, CSD) for the co-delivery of doxorubicin (DOX) and STAT3 inhibitor nifuroxazide (NIF) in metastatic melanoma treatment. The superior affinity between CS and overexpressed CD44 receptors in B16F10 cells resulted in 3.3-fold enhancement of cellular uptake compared to free DOX. CSD@DNLP maintained structural stability in physiological conditions, while achieving 75.15% cumulative release within 48 h under a tumor-mimic concentration of glutathione (GSH, 20 mM). Synergistic effects were observed through NIF-mediated STAT3 phosphorylation blockade and DOX-induced DNA damage, resulting in 3.2-fold enhancement in apoptotic cells versus free drugs. In lung metastasis mice, CSD@DNLP suppressed metastatic nodule formation (36% of free DOX + NIF) via dual downregulation of matrix metalloproteinases-2 (MMP-2) and metalloproteinases-2 (MMP-9). This CS-functionalized GSH-responsive lipid-nanoparticle demonstrates a promising strategy in metastatic melanoma.

Keywords:  Chondroitin sulfate; Combination therapy; GSH-responsive release; Metastatic melanoma; STAT3

DOI:  https://doi.org/10.1016/j.ijpharm.2026.126989
Food Sci Biotechnol. 2026 Jun;35(7): 1719-1743

Exploring the nutritional and bioactive potential of microalgal sulfated polysaccharides for functional food applications.

Fajar Sofyantoro, Eka Sunarwidhi Prasedya, Fahrul Nurkolis, Andri Frediansyah.

  Sulfated polysaccharides (SPLs) derived from marine microalgae are gaining attention as bioactive compounds with substantial potential in functional foods. Unlike macroalgal SPLs, microalgal SPLs offer greater structural diversity, owing to unique monosaccharides such as galactose, fucose, xylose, rhamnose, and arabinose, along with distinct sulfation patterns that enhance their bioactivity. These compounds demonstrate significant antioxidative, immunomodulatory, anticancer, and antiviral properties, particularly in genera like Porphyridium and Isochrysis, highlighting their nutraceutical promise. As sustainable, plant-based ingredients, microalgal SPLs meet the rising demand for fortified foods and dietary supplements. Despite their potential, challenges remain in scaling extraction processes, understanding structure-function relationships, and ensuring stability in food products. This review examines the latest advancements in microalgal SPL research, their potential in next-generation functional foods, and the obstacles to their commercialization.

Keywords:  Bioactive compounds; Functional foods; Microalgae; Nutraceuticals; Sulfated polysaccharides; Sustainable food innovation

DOI:  https://doi.org/10.1007/s10068-025-02031-6
J Sci Food Agric. 2026 May 20.

Impact of sulfate groups on the physicochemical properties of Fucoidan from Lessonia trabeculata.

Ping Zou, Xia Yang, Ping Zhao, Jiayi Wang, Bo Zhu.

   BACKGROUND: The bioactivities of polysaccharides are closely associated with their molecular architecture, where factors including molecular weight, monosaccharide composition, sulfate content and other structural characteristics significantly affect their potential applications. Lessonia trabeculata is an important economic brown alga. The structure of fucoidan extracted from L. trabeculata (LTF) and its potential applications in the food industry warrant further investigation.
RESULTS: Fucoidan extracted and purified from L. trabeculata was a sulfated heteropolysaccharide with a molecular weight of 33.4 kDa and a sulfate content of 34.7%. The structure of LTF was characterized based on monosaccharide composition, methylation analysis and nuclear magnetic resonance spectroscopy. The backbone of LTF was composed of →4)-β-d-Xylp-(1→3)-β-l-Fucp-(1→residues, and alternating →2)-β-l-Fucp-(1→3)-β-l-Fucp-(1→, in which the β-l-Fucp residues were either 4-O-sulfated or substituted with α-d-Manp side chains. Additionally, an alternating →3)-α-l-Fucp-(1→4)-α-l-Fucp (2-O-sulfated)-(1→ sequence existed as a secondary chain). In addition, the present study found that native LTF exhibited superior moisture absorption, moisture retention, oil-holding, water-holding capacities and emulsifying activity relative to deS-LTF. Overall, our results indicated that sulfate groups in LTF significantly affect its functional properties.
CONCLUSION: This study demonstrates the potential of LTF as a promising emulsifier in the food and cosmetic industries. These findings provide a theoretical basis for the practical application of LTF in related fields. © 2026 Society of Chemical Industry.

Keywords:  Lessonia trabeculata; emulsion properties; fucoidan; moisture absorption; sulfate content

DOI:  https://doi.org/10.1002/jsfa.70726
Pediatr Nephrol. 2026 May 19.

Sulfate handling in proximal renal tubular defects: an exploratory study.

Emil den Bakker, Miriam Wamelink, Desiree E C Smith, Elena N Levtchenko, Arend Bökenkamp.

   BACKGROUND: Renal tubular disease causes loss of electrolytes and other molecules. One of these electrolytes is inorganic sulfate, which is reabsorbed by dedicated transporters, including NaS1, encoded by the SLC13A1 gene. Still, inorganic sulfate is rarely measured in clinical practice, although it is essential for the development and functioning of several organ systems. The importance of adequate sulfate stores is emphasized by genetic disorders impairing sulfate metabolism in the brain, bone, and the endocrine system, causing severe neurodevelopmental disorders, skeletal dysplasia, and hormonal imbalance. Low availability due to renal loss of inorganic sulfate has also been linked to these disorders. We aimed to assess the prevalence of renal inorganic sulfate wasting in renal tubular diseases in a small cohort as an exploratory study.
METHODS: Inorganic sulfate was measured in serum and urine of patients with proximal renal tubular disorders using remnant material obtained during routine check-ups. Fractional excretion of inorganic sulfate was calculated alongside plasma inorganic sulfate concentrations and cystatin C-based eGFR.
RESULTS: Fourteen patients were included, in whom 1 to 4 paired measurements of urine and plasma inorganic sulfate were available. Five patients had decreased plasma sulfate on at least one occasion; 13 patients had increased fractional excretion in at least one measurement. In patients with cystinosis, during cysteamine treatment plasma inorganic sulfate levels were often normal despite increased fractional excretion.
CONCLUSIONS: Increased inorganic sulfate loss is prevalent in children with proximal tubular defects and sulfate stores can be repleted by oral drugs like cysteamine.

Keywords:  Cystinosis; Dent disease; Lowe syndrome; Sulfate

DOI:  https://doi.org/10.1007/s00467-026-07359-7
Carbohydr Polym. 2026 Aug 01. pii: S0144-8617(26)00543-6. [Epub ahead of print]385 125426

pH-responsive, self-lubricating hyaluronic acid-chondroitin sulfate-chitosan hydrogel for articular cartilage repair.

Haofeng Qiu, Jingfang Zheng, Zheyu Yao, Ximing Cai, Gaoke Pan, Xufeng Mao, Xin Zhao, Lei Shao, Dangsheng Xiong, Rong Wang, Yi Zhang.

  Cartilage degradation after joint injury often leads to post-traumatic osteoarthritis, a process accompanied by a drop in synovial pH. Traditional dynamically crosslinked hydrogels overlook how their mechanical and tribological properties change in such acidic, inflammatory environments. Here, we report an arthritis-responsive, injectable hydrogel designed to both regenerate articular cartilage and inhibit its further degradation. The hydrogel is formed via Schiff base chemistry between aldehyde groups of oxidized hyaluronic acid (OHA) and amino groups of adipic acid dihydrazide-grafted chondroitin sulfate (Chs-ADH) and carboxyethyl chitosan (CEC). Under neutral pH, the imine bonds remain stable, allowing precise defect filling and minimizing stress-induced debris; under acidic conditions, their reversible nature enhances lubrication and resists wear. The hydrogel formulation was optimized using molecular dynamics simulations to achieve excellent injectability, shear-thinning behavior, and low friction without impeding normal joint motion. In vitro, the hydrogel exhibited outstanding biocompatibility and stimulated cell migration. In vivo, it accelerated cartilage repair, prevented cartilage degradation, and restored the lubrication of newly formed tissue to levels comparable with healthy cartilage. Together, these findings demonstrate that the pH-sensitive hydrogel is a promising candidate for effective cartilage repair and prevention of cartilage degradation.

Keywords:  Cartilage regeneration; Lubrication; Molecular dynamics simulation; Responsive hydrogel

DOI:  https://doi.org/10.1016/j.carbpol.2026.125426
Nat Commun. 2026 May 19.

Oxysterol undersulfation promotes osteoarthritis by fueling chondrocyte lipid accumulation.

Huanbo Wang, Bowei Ni, Yu Qian, Guangyu Ding, Ting He, Xinyu Zhang, Hailun Xu, Xue Hao, Yaqian Hu, Di Wang, Qiang Jie, Ying Li, Tianyang Jie, Zhong Alan Li, Zhuojing Luo, Houfeng Zheng, Liu Yang, Chao Zheng.

Osteoarthritis (OA) is a common degenerative joint disease with no curative treatments and a poorly understood etiology. Here, we report that defective sulfation, a largely underexplored chemical modification of lipid metabolites, drives pathogenic lipid accumulation in chondrocytes to promote OA. Intrigued by observations of lipid droplet accumulation in cartilage from genetically modified male mice with sulfation defects, we identified that the production and sulfation status of 25-hydroxycholesterol (25HC), an oxysterol metabolite, could impact OA risk and development. Transcriptomics and peptide-centric local stability assays revealed that 25HC and its sulfated derivative (25HC3S) exhibited opposing regulatory effects on lipid biosynthesis genes and distinct protein interaction profiles. Mechanistically, 25HC activated Liver X Receptor (LXR) ligand-dependently to potentiate lipid synthesis and uptake, while 25HC3S deactivated LXR by altering its nuclear localization and promoting nucleolar sequestration, thus mitigating chondrocyte lipid accumulation and cartilage damage. Moreover, human studies linked genetic variants in 25HC sulfation pathways to OA risk, with concomitantly reduced sulfation gene expression and increased lipid accumulation in OA cartilage. These findings support an oxysterol undersulfation model wherein defective oxysterol sulfation unleashes nuclear oxysterol receptor activation to drive pathogenic chondrocyte lipid accumulation, and highlight the therapeutic potential of 25HC3S against OA.

DOI: https://doi.org/10.1038/s41467-026-73322-7