Biochemical Journal最新文献

{"title":"Structural and biophysical studies of human E3 ligase Deltex 4.","authors":"Milan M Fowkes, Jonathan M Elkins","doi":"10.1042/BCJ20260406","DOIUrl":"https://doi.org/10.1042/BCJ20260406","url":null,"abstract":"<p><p>Deltex E3 ligases such as DTX1 and DTX2 are known to bind to ADP-ribosylated substrates and consequently ubiquitinate them. However, little is known about the role of the deltex E3 ligase DTX4 in substrate binding and ubiquitination. Here, we present the crystal structure of the DTX4 RING-DTC domains in complex with ADP-ribose to a final resolution of 2.8 Å and uncover a unique domain swap within the RING domain. Structural comparison with the closely related RING-DTC domains of DTX1 and DTX2 reveals similarities but also differences in the mode of ligand binding and the number and type of conserved residues. Biophysical assays to assess the strength of binding to nucleotide units of poly-ADP-ribose (PAR) demonstrate a preference for binding to ADP-ribose, strengthening existing evidence for PAR binding. Collectively, the structural and binding data offer insights into the active structure of DTX4 and its interaction with nucleotide units of PAR.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting CLK1 by CRISPR tools and pharmacological inhibition modulates the innate immune response and dengue virus replication.","authors":"Berta Pozzi, Agustina Magalí Lucero, Valeria Buggiano, Miguel Angel Pelaez, Cybele Garcia, Anabella Srebrow","doi":"10.1042/BCJ20260367","DOIUrl":"https://doi.org/10.1042/BCJ20260367","url":null,"abstract":"<p><p>Alternative splicing is a key regulatory mechanism known to be altered upon viral infection. These alterations can arise both from direct viral interference with the splicing machinery and from cellular responses such as activation of innate immunity. Here, we investigated splicing changes shared between dengue virus (DENV) infection and interferon (IFN) treatment in cultured cells, the latter serving as a model for virus-independent innate immune activation. Among the common events, we identified an increased production of non-coding mRNA isoforms from the CLK1 gene, which gives rise to a kinase that phosphorylates splicing factors including SR proteins and spliceosomal components. Consistent with this finding, IFN treatment led to a reduction in CLK1 protein levels. Using stable cell lines with CRISPR/dCas9-mediated modulation of CLK1 expression, we found that silencing CLK1 enhanced the induction of immune response genes, while its over-expression attenuated it. Inhibition of CLK1 kinase activity with the pharmacological inhibitor TG003 further potentiated IFN-induced gene expression and reduced DENV replication. Altogether, these results identify CLK1 as a proviral negative regulator of IFN-stimulated gene expression and suggest that its inhibition could enhance antiviral defenses and become a target for therapeutic strategies.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and Functional Consequences of Arg512 Mutations in Methyl-CpG-Binding Domain Protein 4.","authors":"Rebecca Barnes, Hala Ouzon-Shubeita, Charlene Mandimutsira, Grace Wang, Seongmin Lee","doi":"10.1042/BCJ20260503","DOIUrl":"https://doi.org/10.1042/BCJ20260503","url":null,"abstract":"<p><p>Methyl-CpG-binding domain protein 4 (MBD4) is a base excision repair glycosylase that removes the thymine of a T:G mispair. If left unrepaired, these mismatches can cause C>T transitions. Human MBD4 uses an arginine finger, R468, to flip the mispaired thymine into its active site and to stabilize the orphaned guanine. MBD4 also possesses a second highly conserved arginine, R512, in close proximity to R468, whose role remains unknown despite an R512W mutation catalogued in colorectal cancers and an R512Q mutation reported in Myelodysplastic Syndromes. Here, we investigate the structural and functional significance of R512 using MBD4 variants R512A, R512K, R512Q, and R512W. We find that the native hydrogen-bonding network mediated by R512 is critical for active-site stability, and that R512K is the only variant to retain catalytic activity. This mutant preserves the wild-type rate of base excision despite a reduced affinity for the DNA substrate. Structural characterization of R512K MBD4 bound to T:G-mismatched DNA reveals an ordered water molecule in this pocket. This water molecule, along with the lysine amino group, retain 6 of the 7 native R512 hydrogen bonds, thereby preserving the local architecture of the enzyme. Comparative structural modeling of the catalytically inactive R512A, R512Q, and R512W variants suggests that loss of localized positive charge combined with disruption of the hydrogen-bonding network accounts for their inactivity. Together, these findings establish an essential role for R512 in catalytic activity and suggest how mutation of this residue can disrupt the BER pathway and contribute to tumorigenesis.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MyoD and Myogenin regulatory cascade is targeted by tumor signals to repress myogenesis in cancer cachexia.","authors":"Kai-Fan Huang, Yi-Shiuan Liao, Huang-Bin Lin, I-Ning Lu, Xin-Ray Lin, Yi-Ju Wu, Huai-Jen Chang, Yu-Ching Huang, Wan-Ting Feng, Po-Hong Chang, Yu-Hsuan Chang, Yu-Xiang Chiang, Ting-Hsiang Lung, Chuan-Che Wu, Tzu-Han Weng, Hsiang-Cheng Chi, Shen-Liang Chen","doi":"10.1042/BCJ20260026","DOIUrl":"https://doi.org/10.1042/BCJ20260026","url":null,"abstract":"<p><p>It is estimated that about 20-30% cancer death is directly linked to the syndrome called cancer cachexia (CAC), which is characterized by debilitating skeletal muscle (SKM) and fat wasting.  Recent studies have found that the myogenic ability of myogenic stem cells (MuSC) in the cachectic SKM is compromised, but the mechanisms remain to be clarified. Using the C26 colon cancer cells mediated cachexia model, the down-regulation of myogenic regulatory factors (MRF) MyoD and MyoG, but not Myf5 and Mrf4, was confirmed in vitro and in vivo.  We further found the repression of myogenesis by C26 cells conditioned medium (C26M) in vitro could be rescued by inducible over-expression of either MyoD or MyoG, but not Myf5 or Mrf4. As MyoD is the major upstream activator of MyoG, these findings suggest the targeting of the MyoD-MyoG regulatory cascade by CAC signals.  The transactivation of myogenic gene promoters by MyoD was also constantly repressed by C26M, suggesting MyoD dysfunction is critical to myogenesis repression in CAC.   The repression of MyoD gene transcription by C26M was found to be mediated by the core enhancer (CE) located in the distal enhancer (DE) region. The activation of CE mediated promoter activity by MyoD, ß-Catenin*, and Pbx1 was significantly reduced by C26M, implying the repression of MyoD positive feedback loop.  Taken together, these observations suggest that CAC signals repress both MyoD transactivational activity on target genes and its transcriptional activation by upstream activators, which subsequently leads to repression of myogenesis and failed regeneration in cachectic SKM.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional and Mechanistic Characterization of SARS-CoV-2 NSP15 Reveals Metal-Dependent Regulation and Inhibition by Direct-Binding Small Molecules.","authors":"Hira Singh Gariya, Sanjay Kumar, Anurag Singh, Raja Mani Tripathi, Imran Ansari, Ravishankar Ramachandran","doi":"10.1042/BCJ20260313","DOIUrl":"https://doi.org/10.1042/BCJ20260313","url":null,"abstract":"<p><p>The SARS-CoV-2 non-structural protein 15 (NSP15) is a uridine-specific endoribonuclease involved in viral RNA processing and immune evasion, thereby contributing to viral pathogenesis. Although NSP15 has been structurally characterized by several studies, which report its endoribonuclease activity and regulatory features, important functional and regulatory gaps remain unaddressed, including quantitative stability, metal-ion regulation, and inhibitor-binding kinetics. To address these gaps, we used an integrated approach to investigate NSP15 regulation and inhibition. Thermochemical stability studies indicated moderate NSP15 stability, with cooperative unfolding characterized by a Cm of 1.68 M urea and a Tm of ~70 °C. Urea PAGE activity measurements revealed a strong metal-ion dependence, with Mn²⁺ as the optimal activator and marked stimulation compared to Ca2+, Mg2+, and Zn2+. Biophysical experiments using SPR and fluorescence quenching confirmed a direct protein-ligand interaction with dissociation constants of ~1-4 µM. Consistent with these results, the compounds inhibited endoribonuclease activity with IC50 values of ~8-30 µM. Alanine substitution of catalytic residues H235A and H250A completely abolished cleavage, while S294A within the B1 pocket, a Uridine-specificity determinant, reduced activity by 51-67% (10-50 nM), markedly weakened inhibitor binding, and increased inhibition susceptibility. Importantly, docking and simulation studies revealed stabilized active-site dynamics driven by strong polar interactions, as evidenced by SASA, hydrogen-bonding analysis, RMSD, RMSF, and radius of gyration (Rg) analyses, underscoring the coordinated contribution of polar contacts and hydrophobic interactions in the inhibitor-bound active-site conformation. Collectively, this work provides quantitative, mutational, and functional characterization, forming a foundation for designing NSP15-specific antivirals.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum albumin oxidation and inter-alpha-trypsin-inhibitor heavy chain-4 abundance correlates with the dystropathology in the rat model of Duchenne muscular dystrophy.","authors":"Angelo Patrick R Bautista, Aude Lafoux, Irene Tsioutsias, Jessica R Terrill, Caroline Le Guiner, Corinne Huchet, Peter G Arthur","doi":"10.1042/BCJ20260160","DOIUrl":"https://doi.org/10.1042/BCJ20260160","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a fatal X‑linked genetic disease caused by the absence of functional dystrophin, resulting in muscle membrane fragility, chronic inflammation, and progressive muscle wasting. The lack of effective treatments is further compounded by the slow onset of measurable changes in clinical outcomes, such as muscle strength, which often take a year or longer to become evident. Blood‑based biomarkers that can predict treatment efficacy and monitor disease progression would significantly accelerate therapeutic development. We propose that oxidative modifications to proteins in blood, a consequence of muscle inflammation, could be used to monitor disease progression in DMD. Using the DMDmdx rat, a model with more severe dystropathology than the mouse model of dystrophy (mdx), we assessed inflammation and oxidative stress in muscle and blood across disease stages. DMDmdx rats aged 1.5-12 months showed sustained immune activation, as indicated by elevated circulating leukocytes and increased myeloperoxidase content in dystrophic muscle compared with wild type. Oxidative protein modifications, including carbonylation, tyrosine chlorination, and thiol oxidation, were significantly elevated in serum and tissues of dystrophic rats. Two proteins showed distinct disease‑associated oxidative changes: albumin, which exhibited consistently increased thiol oxidation across ages, and inter‑alpha trypsin inhibitor 4 (ITIH4), which showed elevated chlorination between 1.5-4.5 months. Notably, serum ITIH4 abundance correlated with markers of muscle inflammation and oxidative stress. These findings identify serum albumin thiol oxidation and serum ITIH4 abundance as promising blood‑based biomarkers for monitoring inflammation‑associated dystropathology in DMD.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of FAD binding to the apo-form of diflavin-linked disulfide oxidoreductase derived from cyanobacterium\u0000 Synechocystis\u0000 sp. PCC6803","authors":"Yu Hirano,Takaaki Suzuki,Naho Umeda,Yu Minato,Kaname Yoshimura,Taro Tamada,Shigenobu Kimura","doi":"10.1042/bcj20260320","DOIUrl":"https://doi.org/10.1042/bcj20260320","url":null,"abstract":"Diflavin-linked disulfide oxidoreductase (DDOR) from the cyanobacterium Synechocystis sp. PCC6803 is an NADPH-thioredoxin reductase (NTR) superfamily enzyme that forms a homodimer containing two FAD molecules (FAD1 and FAD2) per monomer. FAD1 is conserved in the NTR superfamily, while FAD2 is characteristic of DDOR. Under aerobic conditions, thiol reduction of DDOR produces an apparently air-stable neutral blue semiquinone, but the respective roles of FAD1 and FAD2 in the reduction process remain unclear. To address this, spectroscopic, structural and mutational analyses were performed to investigate the contributions of the two FAD molecules. Recombinant apo- and holo-DDOR synthesised in Escherichia coli cells were separated and purified. Fluorescence titration of the apo-DDOR with FAD revealed rapid binding of two FADs. Stopped-flow analysis indicated biphasic binding of FAD to apo-DDOR. X-ray crystal structures of apo- and holo-DDORs exhibited pronounced conformational differences in the FAD-binding sites, suggesting that the first FAD may bind to the FAD1-binding site and subsequently induce formation of the FAD2-binding site. Systematic replacement of amino acid residues in the FAD2-binding site showed that mutations at the characteristic loop region bearing the GKKDSLY motif resulted in binding of three flavin species of FAD, flavin mononucleotide and riboflavin. Moreover, replacement of both Trp53 and Tyr143 at the binding site of the isoalloxazine ring of FAD2 with Ala residues yielded exclusively the apo-form. These results indicate that the loop region restricts the flavin species bound at the FAD2-binding site, and Trp53 and Tyr143 are important for FAD binding to both the FAD1- and FAD2-binding sites.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"26 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Galactosyl residues on Trypanosoma cruzi trypomastigote glycoconjugates contribute to host-cell invasion via Galectin-3 and Annexin A2-S100A10 complex.","authors":"Luciane Ganiko, Ernesto S Nakayasu, Marina da Silva Ferreira, Luiz S Silva, Alexandre F Marques, Priscila S G Farani, Igor C Almeida","doi":"10.1042/BCJ20260011","DOIUrl":"https://doi.org/10.1042/BCJ20260011","url":null,"abstract":"<p><p>Linear, nonreducing terminal a-galactopyranosyl (a-Gal) epitopes are displayed on the major surface glycosylphosphatidylinositol (GPI)-anchored glycoconjugates of infective Trypanosoma cruzi trypomastigotes, the agent of Chagas disease (CD). These immunodominant epitopes elicit abundant (3-5% of circulating IgG), trypanolytic CD anti-a-Gal antibodies, yet their role on the parasite surface remains elusive. Here, affinity purification of macrophage extracts on the immobilized Galα1-3Galβ1-4GlcNAcβ (Galili's aGal epitope) identified Galectin-3 (Gal-3) and the annexin A2-S100A10 heterotetramer (A2t) as candidate host-cell receptors, whose specificities were mapped against glycoconjugates and parasite-derived molecules. Gal-3 bound a-Gal-bearing neoglycoproteins (α-Gal-NGPs), the glycosphingolipid (GSL) iGb3 (Galα1-3Galβ1-4Glcβ1-1-Cer), trypomastigote-derived GPI-mucins (tGPI-mucins), and glycoinositolphospholipids (tGIPLs).  α-Galactosidase abolished Gal-3 binding to trypomastigotes; epimastigote binding was reduced only by β-galactosidase. Conversely, A2t bound galactosylated GSLs in calcium-dependent manner, most strongly Gb4 (GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1-Cer), but not α-Gal-NGPs, and only two of 442 glycans on a printed array gave signals above background, indicating lipid-dependent recognition. A2t recognized the phospholipid-enriched fractions of both developmental stages equally, the tGIPL fraction of trypomastigotes only, and not tGPI-mucins. Antibody blockade of surface Anx2, S100A10, or Gal-3, competition with the soluble proteins, and RNA interference reduced macrophage infection by 29 to 50%, about 53%, and 42 to 59%, respectively. Terminal a-Gal epitopes on major trypomastigote GPI-anchored glycoconjugates therefore contribute to host-cell invasion, chiefly through Gal-3, whereas A2t engages a broader set of lipid-associated ligands; both contribute to a redundant entry repertoire rather than acting as obligate receptors. These interactions may offer targets for vaccine and chemotherapeutic development and serve as diagnostic and prognostic biomarkers in CD.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-resolution profiling of bacterial transcriptomes by SEnd-seq.","authors":"Xiangwu Ju, Shixin Liu","doi":"10.1042/BCJ20250251","DOIUrl":"10.1042/BCJ20250251","url":null,"abstract":"<p><p>Transcription-the process by which genomic DNA is converted into RNA-is a highly dynamic and tightly controlled process across all domains of life. Although bacteria were once regarded as relatively simple organisms, their transcriptomes are now recognized to be remarkably complex, heterogeneous, and subject to multilayered regulation. Despite the availability of an abundance of sequenced bacterial genomes, a comprehensive understanding of how bacteria tune their transcriptional output to adapt to changing environments remains lacking. To this end, SEnd-seq (simultaneous 5' and 3' end sequencing) was developed as a high-throughput approach uniquely capable of simultaneously capturing both 5' and 3' ends of individual RNA molecules, enabling the reconstruction of full-length transcripts. By capturing each RNA molecule as a distinct molecular entity with single-nucleotide resolution, SEnd-seq has uncovered previously unrecognized transcriptional features across diverse bacterial species, including even the well-studied Escherichia coli. This method performs robustly across a wide range of RNA species and organisms, including hard-to-lyse pathogens such as Mycobacterium tuberculosis. Moreover, SEnd-seq exhibits high sensitivity for detecting low-abundance RNA and is compatible with various target RNA enrichment strategies, as well as genetic, chemical, and functional perturbations, enabling context-specific transcriptomic analyses. As a versatile and broadly adaptable technology, SEnd-seq provides comprehensive insights into transcriptional regulation, RNA processing, and the coordination between RNA-based processes, thereby uncovering potential targets for antibiotic development. In the present review, we summarize the features and applications of SEnd-seq and discuss its future methodological development and expansion into broader biological and biomedical research contexts.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"483 9","pages":"1713-1727"},"PeriodicalIF":3.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13500782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reshaping the glycocalyx: the SULF extracellular endosulfatases as molecular editors of heparan Sulfate.","authors":"Rebecca-Joe Boustany,Sylvain D Vallet,Yara Awad,Evelyne Gout,Rebekka Wild,Romain R Vivès","doi":"10.1042/bcj20260351","DOIUrl":"https://doi.org/10.1042/bcj20260351","url":null,"abstract":"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.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"143 1","pages":"1437-1456"},"PeriodicalIF":4.1,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}