{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T16:59:43Z","timestamp":1782406783814,"version":"3.54.5"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002345","name":"Eberhard Karls Universit\u00e4t T\u00fcbingen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002345","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The deposition of circulating complement factor H-related (FHR) proteins in tissues around the body has been implicated in a series of complement-mediated diseases. However, the array of blood-borne binding partners with which they interact remains unclear. Here, we identify novel blood-borne binding partners of FHR proteins, firstly through preliminary untargeted immunoprecipitation and mass spectrometry, and subsequently validating direct interactions through solid-phase binding assays. We uncover direct interactions between FHRs and soluble immune mediators including complement C4 (C4), cathepsin G (CTSG), mannose-binding lectin 2 (MBL2), and platelet basic protein (PPBP). Functional assays show that FHR-1 and FHR-2 attenuate CTSG-mediated C3b degradation, while FHR-5 and FHL-1 appear to affect lectin pathway activation via MBL2 binding. These interactions suggest that FHRs perhaps confer activity not only through surface competition with factor H, but also via selective engagement with circulating ligands. Our findings expand the known FHR interactome and reveal potential new avenues for understanding FHR biology and targeting complement dysregulation in disease.<\/jats:p>","DOI":"10.1038\/s41598-026-44779-9","type":"journal-article","created":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T20:35:55Z","timestamp":1774211755000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of novel blood-borne soluble binding partners of factor H-related proteins"],"prefix":"10.1038","volume":"16","author":[{"given":"Jiaqi","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Woerz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Boldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonika","family":"Rathi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasse","family":"Wolfram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Ueffing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"44779_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-021-00892-7","author":"RB Pouw","year":"2021","unstructured":"Pouw, R. B. & Ricklin, D. Tipping the balance: intricate roles of the complement system in disease and therapy. Seminars Immunopathol. https:\/\/doi.org\/10.1007\/s00281-021-00892-7 (2021).","journal-title":"Seminars Immunopathol."},{"key":"44779_CR2","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/nri2620","volume":"9","author":"PF Zipfel","year":"2009","unstructured":"Zipfel, P. F. & Skerka, C. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9, 729\u2013740 (2009).","journal-title":"Nat. Rev. Immunol."},{"key":"44779_CR3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.596415","author":"M Mannes","year":"2020","unstructured":"Mannes, M., Dopler, A., Huber-Lang, M. & Schmidt, C. Q. Tuning the Functionality by Splicing: Factor H and Its Alternative Splice Variant FHL-1 Share a Gene but Not All Functions. Front. Immunol. https:\/\/doi.org\/10.3389\/fimmu.2020.596415 (2020).","journal-title":"Front. Immunol."},{"key":"44779_CR4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nchembio.1696","volume":"11","author":"BS Blaum","year":"2015","unstructured":"Blaum, B. S. et al. Structural basis for sialic acid-mediated self-recognition by complement factor H. Nat. Chem. Biol. 11, 77\u201382 (2015).","journal-title":"Nat. Chem. Biol."},{"key":"44779_CR5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00025","author":"A Langford-Smith","year":"2015","unstructured":"Langford-Smith, A., Day, A. J., Bishop, P. N. & Clark, S. J. Complementing the sugar code: Role of GAGs and sialic acid in complement regulation. Front. Immunol. https:\/\/doi.org\/10.3389\/fimmu.2015.00025 (2015).","journal-title":"Front. Immunol."},{"key":"44779_CR6","doi-asserted-by":"publisher","first-page":"5663","DOI":"10.4049\/jimmunol.155.12.5663","volume":"155","author":"S K\u00fchn","year":"1995","unstructured":"K\u00fchn, S., Skerka, C. & Zipfel, P. F. Mapping of the complement regulatory domains in the human factor H-like protein 1 and in factor H1. J. Immunol. 155, 5663\u20135670 (1995).","journal-title":"J. Immunol."},{"key":"44779_CR7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1135490","volume":"15","author":"N S\u00e1ndor","year":"2024","unstructured":"S\u00e1ndor, N. et al. The human factor H protein family \u2013 An update. Front. Immunol. 15, 1135490 (2024).","journal-title":"Front. Immunol."},{"key":"44779_CR8","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0162-3109(99)00015-6","volume":"42","author":"PF Zipfel","year":"1999","unstructured":"Zipfel, P. F., Jokiranta, S., Hellwage, T., Koistinen, J. & Meri, S. The Factor H Protein Family. Immunopharmacology 42, 53\u201360 (1999).","journal-title":"Immunopharmacology"},{"key":"44779_CR9","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.molimm.2013.06.001","volume":"56","author":"C Skerka","year":"2013","unstructured":"Skerka, C., Chen, Q., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement factor H related proteins (CFHRs). Mol. Immunol. 56, 170\u2013180 (2013).","journal-title":"Mol. Immunol."},{"key":"44779_CR10","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/imr.13166","volume":"313","author":"L Lucientes-Continente","year":"2023","unstructured":"Lucientes-Continente, L., M\u00e1rquez-Tirado, B. & de Goicoechea Jorge, E. The factor H protein family: The switchers of the complement alternative pathway. Immunol. Rev. 313, 25\u201345 (2023).","journal-title":"Immunol. Rev."},{"key":"44779_CR11","doi-asserted-by":"publisher","first-page":"2439","DOI":"10.1182\/blood-2009-02-205641","volume":"114","author":"S Heinen","year":"2009","unstructured":"Heinen, S. et al. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 114, 2439\u20132447 (2009).","journal-title":"Blood"},{"key":"44779_CR12","doi-asserted-by":"publisher","first-page":"4685","DOI":"10.1073\/pnas.1219260110","volume":"110","author":"EG de Jorge","year":"2013","unstructured":"de Jorge, E. G. et al. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proc. Natl. Acad. Sci. U. S. A. 110, 4685\u20134690 (2013).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"44779_CR13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01328","volume":"8","author":"AE van Beek","year":"2017","unstructured":"van Beek, A. E. et al. Factor H-related (FHR)-1 and FHR-2 form homo- and heterodimers, while FHR-5 circulates only as homodimer in human plasma. Front. Immunol. 8, 1328 (2017).","journal-title":"Front. Immunol."},{"key":"44779_CR14","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.it.2008.04.008","volume":"29","author":"M J\u00f3zsi","year":"2008","unstructured":"J\u00f3zsi, M. & Zipfel, P. F. Factor H family proteins and human diseases. Trends Immunol. 29, 380\u2013387 (2008).","journal-title":"Trends Immunol."},{"key":"44779_CR15","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/ng.3448","volume":"48","author":"LG Fritsche","year":"2016","unstructured":"Fritsche, L. G. et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat. Genet. 48, 134\u2013143 (2016).","journal-title":"Nat. Genet."},{"key":"44779_CR16","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1038\/ng.976","volume":"43","author":"S Raychaudhuri","year":"2011","unstructured":"Raychaudhuri, S. et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet. 43, 1232\u20131236 (2011).","journal-title":"Nat. Genet."},{"key":"44779_CR17","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/ng0710-553","volume":"42","author":"S Raychaudhuri","year":"2010","unstructured":"Raychaudhuri, S. et al. Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat. Genet. 42, 553\u2013555 (2010).","journal-title":"Nat. Genet."},{"key":"44779_CR18","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.molimm.2014.06.032","volume":"61","author":"EC Schramm","year":"2014","unstructured":"Schramm, E. C. et al. Genetic variants in the complement system predisposing to age-related macular degeneration: A review. Mol. Immunol. 61, 118\u2013125 (2014).","journal-title":"Mol. Immunol."},{"key":"44779_CR19","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1016\/j.ajhg.2021.05.015","volume":"108","author":"V Cipriani","year":"2021","unstructured":"Cipriani, V. et al. Beyond Factor H: the influence of genetic variation with age-related macular degeneration on circulating Factor H-like 1 and Factor H-related protein levels. Am. J. Hum. Genet. 108, 1385\u20131400 (2021).","journal-title":"Am. J. Hum. Genet."},{"key":"44779_CR20","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/j.ajhg.2021.06.002","volume":"108","author":"L Lor\u00e9s-Motta","year":"2021","unstructured":"Lor\u00e9s-Motta, L. et al. Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration. Am. J. Hum. Genet. 108, 1367\u20131384 (2021).","journal-title":"Am. J. Hum. Genet."},{"issue":"1","key":"44779_CR21","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/s41467-020-14499-3","volume":"11","author":"V Cipriani","year":"2020","unstructured":"Cipriani, V. et al. Increased circulating levels of Factor H-related protein 4 are strongly associated with age-related macular degeneration. Nat. Commun. 11778. (2020).","journal-title":"Nat. Commun."},{"key":"44779_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-023-44605-0","volume":"15","author":"MA Zouache","year":"2024","unstructured":"Zouache, M. A. et al. Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression. Nat. Commun. 15, 1\u201317 (2024).","journal-title":"Nat. Commun."},{"key":"44779_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2025.110343","volume":"255","author":"SJ Clark","year":"2025","unstructured":"Clark, S. J. et al. Breaking Bruch\u2019s: How changes in Bruch\u2019s membrane influence retinal homeostasis. Exp. Eye Res. 255, 110343 (2025).","journal-title":"Exp. Eye Res."},{"key":"44779_CR24","doi-asserted-by":"publisher","first-page":"7488","DOI":"10.1038\/s41598-024-56661-7","volume":"14","author":"L Wolfram","year":"2024","unstructured":"Wolfram, L. et al. The impact of substrate stiffness on morphological, transcriptional and functional aspects in RPE. Sci Rep 14, 7488 (2024).","journal-title":"Sci Rep"},{"key":"44779_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-025-03499-z","volume":"22","author":"A Sekulic","year":"2025","unstructured":"Sekulic, A. et al. Factor-H-related protein 1 (FHR1), a promotor of para-inflammation in age-related macular degeneration. J. Neuroinflamm. 22, 1\u201324 (2025).","journal-title":"J. Neuroinflamm."},{"key":"44779_CR26","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1080\/07853890601097030","volume":"38","author":"GS Hageman","year":"2006","unstructured":"Hageman, G. S. et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann. Med. 38, 592\u2013604 (2006).","journal-title":"Ann. Med."},{"key":"44779_CR27","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1038\/ng1890","volume":"38","author":"AE Hughes","year":"2006","unstructured":"Hughes, A. E. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat. Genet. 38, 1173\u20131177 (2006).","journal-title":"Nat. Genet."},{"key":"44779_CR28","doi-asserted-by":"publisher","first-page":"4694","DOI":"10.1093\/hmg\/ddq399","volume":"19","author":"LG Fritsche","year":"2010","unstructured":"Fritsche, L. G. et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum. Mol. Genet. 19, 4694\u20134704 (2010).","journal-title":"Hum. Mol. Genet."},{"key":"44779_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61193-3","volume":"16","author":"MP Reeve","year":"2025","unstructured":"Reeve, M. P. et al. Loss of CFHR5 function reduces the risk for age-related macular degeneration. Nat. Commun. 16, 5766 (2025).","journal-title":"Nat. Commun."},{"key":"44779_CR30","doi-asserted-by":"publisher","first-page":"3187","DOI":"10.1681\/ASN.2015111210","volume":"27","author":"J Xie","year":"2016","unstructured":"Xie, J. et al. Fine mapping implicates a deletion of CFHR1 and CFHR3 in protection from IgA nephropathy in Han Chinese. J. Am. Soc. Nephrol. 27, 3187\u20133194 (2016).","journal-title":"J. Am. Soc. Nephrol."},{"key":"44779_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-025-03589-1","volume":"15","author":"NK Banda","year":"2025","unstructured":"Banda, N. K. et al. Analysis of human factor H-related gene and protein expressed in rheumatoid arthritis synovium identifies a novel mechanism promoting dysregulated complement pathway activation. Sci. Rep. 15, 1\u201318 (2025).","journal-title":"Sci. Rep."},{"key":"44779_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2023.100701","volume":"23","author":"F Woerz","year":"2024","unstructured":"Woerz, F. et al. Interactome analysis reveals a link of the novel ALMS1-CEP70 complex to centrosomal clusters. Mol. Cell. Proteomics 23, 100701 (2024).","journal-title":"Mol. Cell. Proteomics"},{"key":"44779_CR33","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1172\/JCI68280","volume":"123","author":"A Tortajada","year":"2013","unstructured":"Tortajada, A. et al. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. J. Clin. Invest. 123, 2434\u20132446 (2013).","journal-title":"J. Clin. Invest."},{"key":"44779_CR34","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/S0014-5793(99)01554-9","volume":"462","author":"J Hellwage","year":"1999","unstructured":"Hellwage, J. et al. Functional properties of complement factor H-related proteins FHR-3 and FHR-4: Binding to the C3d region of C3b and differential regulation by heparin. FEBS Lett. 462, 345\u2013352 (1999).","journal-title":"FEBS Lett."},{"key":"44779_CR35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01607","volume":"9","author":"P S\u00e1nchez-Corral","year":"2018","unstructured":"S\u00e1nchez-Corral, P., Pouw, R. B., L\u00f3pez-Trascasa, M. & J\u00f3zsi, M. Self-damage caused by dysregulation of the complement alternative pathway: Relevance of the Factor H protein family. Front. Immunol. 9, 1607 (2018).","journal-title":"Front. Immunol."},{"key":"44779_CR36","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/S0049-3848(99)00242-X","volume":"98","author":"A Bonnefoy","year":"2000","unstructured":"Bonnefoy, A. & Legrand, C. Proteolysis of Subendothelial Adhesive Glycoproteins(Fibronectin, Thrombospondin, and von Willebrand) by Plasmin, Leukocyte Cathepsin G, and Elastase. Thromb. Res. 98, 323 (2000).","journal-title":"Thromb. Res."},{"key":"44779_CR37","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1016\/j.bbrc.2018.07.038","volume":"503","author":"NS Gudmann","year":"2018","unstructured":"Gudmann, N. S. et al. Lung tissue destruction by Proteinase 3 and Cathepsin G mediated elastin degradation is elevated in chronic obstructive pulmonary disease. Biochem. Biophys. Res. Commun. 503, 1284\u20131290 (2018).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"44779_CR38","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.jdermsci.2008.08.004","volume":"53","author":"ZR L\u00fc","year":"2009","unstructured":"L\u00fc, Z. R. et al. Cathepsin G increases MMP expression in normal human fibroblasts through fibronectin fragmentation, and induces the conversion of proMMP-1 to active MMP-1. J. Dermatol. Sci. 53, 146\u2013150. https:\/\/doi.org\/10.1016\/j.jdermsci.2008.08.004 (2009).","journal-title":"J. Dermatol. Sci."},{"key":"44779_CR39","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1034\/j.1600-065X.2001.1800108.x","volume":"180","author":"DL Jack","year":"2001","unstructured":"Jack, D. L., Klein, N. J. & Turner, M. W. Mannose-binding lectin: Targeting the microbial world for complement attack and opsonophagocytosis. Immunol. Rev. 180, 86\u201399. https:\/\/doi.org\/10.1034\/j.1600-065X.2001.1800108.x (2001).","journal-title":"Immunol. Rev."},{"key":"44779_CR40","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1111\/j.1348-0421.2011.00378.x","volume":"55","author":"K Tateishi","year":"2011","unstructured":"Tateishi, K. & Matsushita, M. Activation of the alternative complement pathway by mannose-binding lectin via a C2-bypass pathway. Microbiol. Immunol. 55, 817\u2013821. https:\/\/doi.org\/10.1111\/j.1348-0421.2011.00378.x (2011).","journal-title":"Microbiol. Immunol."},{"key":"44779_CR41","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.1002\/eji.200324401","volume":"34","author":"A Roos","year":"2004","unstructured":"Roos, A. et al. Antibody-mediated activation of the classical pathway of complement may compensate for mannose-binding lectin deficiency. Eur. J. Immunol. 34, 2589\u20132598 (2004).","journal-title":"Eur. J. Immunol."},{"key":"44779_CR42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145419","author":"M Dai","year":"2015","unstructured":"Dai, M. et al. Identification and functional characterization of glycosylation of recombinant human platelet-derived growth factor-BB in Pichia pastoris. PLoS One https:\/\/doi.org\/10.1371\/journal.pone.0145419 (2015).","journal-title":"PLoS One"},{"key":"44779_CR43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.845953","volume":"13","author":"A Papp","year":"2022","unstructured":"Papp, A. et al. Complement factor H-related proteins FHR1 and FHR5 interact with extracellular matrix ligands, reduce factor H regulatory activity and enhance complement activation. Front. Immunol. 13, 845953 (2022).","journal-title":"Front. Immunol."},{"key":"44779_CR44","doi-asserted-by":"publisher","first-page":"921","DOI":"10.4049\/jimmunol.147.3.921","volume":"147","author":"CM Maison","year":"1991","unstructured":"Maison, C. M., Villiers, C. L. & Colomb, M. G. Proteolysis of C3 on U937 cell plasma membranes. Purification of cathepsin G. J. Immunol. 147, 921\u2013926 (1991).","journal-title":"J. Immunol."},{"key":"44779_CR45","first-page":"731","volume":"15","author":"U Narendra","year":"2009","unstructured":"Narendra, U., Pauer, G. J. T. & Hagstrom, S. A. Genetic analysis of complement factor H related 5, CFHR5, in patients with age-related macular degeneration. Mol. Vis. 15, 731\u2013736 (2009).","journal-title":"Mol. Vis."},{"key":"44779_CR46","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1016\/j.ajhg.2025.03.016","volume":"112","author":"AM Holleman","year":"2025","unstructured":"Holleman, A. M. et al. Rare predicted loss-of-function and damaging missense variants in CFHR5 associate with protection from age-related macular degeneration. Am. J. Hum. Genet. 112, 1062\u20131080 (2025).","journal-title":"Am. J. Hum. Genet."},{"key":"44779_CR47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00411","volume":"11","author":"TS Zamolodchikova","year":"2020","unstructured":"Zamolodchikova, T. S., Tolpygo, S. M. & Svirshchevskaya, E. V. Cathepsin G\u2014Not only inflammation: The immune protease can regulate normal physiological processes. Front. Immunol. 11, 512219 (2020).","journal-title":"Front. Immunol."},{"key":"44779_CR48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2118510119","author":"S Mcharg","year":"2022","unstructured":"Mcharg, S. et al. Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26. Proc. Natl. Acad. Sci. U. S. A. https:\/\/doi.org\/10.1073\/pnas.2118510119 (2022).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"44779_CR49","doi-asserted-by":"publisher","first-page":"4962","DOI":"10.4049\/jimmunol.1401613","volume":"193","author":"SJ Clark","year":"2014","unstructured":"Clark, S. J. et al. Identification of Factor H\u2013like Protein 1 as the predominant complement regulator in Bruch\u2019s Membrane: Implications for Age-Related Macular Degeneration. J. Immunol. 193, 4962\u20134970 (2014).","journal-title":"J. Immunol."},{"key":"44779_CR50","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1016\/j.kint.2022.07.035","volume":"102","author":"B Renner","year":"2022","unstructured":"Renner, B. et al. Factor H related proteins modulate complement activation on kidney cells. Kidney Int. 102, 1331\u20131344 (2022).","journal-title":"Kidney Int."},{"key":"44779_CR51","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.676662","volume":"12","author":"MA Loeven","year":"2021","unstructured":"Loeven, M. A. et al. Selective binding of heparin\/heparan sulfate oligosaccharides to Factor H and Factor H-Related Proteins: Therapeutic potential for C3 glomerulopathies. Front. Immunol. 12, 3322 (2021).","journal-title":"Front. Immunol."},{"key":"44779_CR52","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1016\/j.molimm.2009.05.005","volume":"46","author":"P Garred","year":"2009","unstructured":"Garred, P., Honor\u00e9, C., Ma, Y. J., Munthe-Fog, L. & Hummelsh\u00f8j, T. MBL2, FCN1, FCN2 and FCN3\u2014The genes behind the initiation of the lectin pathway of complement. Mol. Immunol. 46, 2737\u20132744 (2009).","journal-title":"Mol. Immunol."},{"key":"44779_CR53","doi-asserted-by":"publisher","first-page":"e22227","DOI":"10.1096\/fj.202101852R","volume":"36","author":"Y Ma","year":"2022","unstructured":"Ma, Y. et al. Mannose-binding lectin activates the nuclear factor-\u03baB and renal inflammation in the progression of diabetic nephropathy. FASEB Journal 36, e22227 (2022).","journal-title":"FASEB Journal"},{"key":"44779_CR54","doi-asserted-by":"publisher","first-page":"e2022722118","DOI":"10.1073\/pnas.2022722118","volume":"118","author":"TH Malik","year":"2021","unstructured":"Malik, T. H. et al. Gain-of-function factor H\u2013related 5 protein impairs glomerular complement regulation resulting in kidney damage. Proc Natl. Acad. Sci. U S A 118, e2022722118 (2021).","journal-title":"Proc Natl. Acad. Sci. U S A"},{"key":"44779_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61193-3","author":"MP Reeve","year":"2024","unstructured":"Reeve, M. P. et al. Loss of CFHR5 function reduces the risk for age-related macular degeneration. medRxiv https:\/\/doi.org\/10.1038\/s41467-025-61193-3 (2024).","journal-title":"medRxiv"},{"key":"44779_CR56","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1002\/gepi.20204","volume":"31","author":"V Dinu","year":"2007","unstructured":"Dinu, V., Miller, P. L. & Zhao, H. Evidence for association between multiple complement pathway genes and AMD. Genet. Epidemiol. 31, 224\u2013237 (2007).","journal-title":"Genet. Epidemiol."},{"key":"44779_CR57","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.molimm.2010.12.016","volume":"48","author":"B Rohrer","year":"2011","unstructured":"Rohrer, B. et al. The alternative pathway is required, but not alone sufficient, for retinal pathology in mouse laser-induced choroidal neovascularization. Mol. Immunol. 48, e1\u2013e8 (2011).","journal-title":"Mol. Immunol."},{"key":"44779_CR58","doi-asserted-by":"publisher","first-page":"156955","DOI":"10.1016\/j.phymed.2025.156955","volume":"145","author":"Y Ding","year":"2025","unstructured":"Ding, Y. et al. Biomarkers and potential mechanisms of Chinese medicine compound (Chuanhong Zhongfeng Capsule) in the treatment of acute cerebral infarction. Phytomedicine 145, 156955 (2025).","journal-title":"Phytomedicine"},{"key":"44779_CR59","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1160\/TH07-01-0046","volume":"97","author":"MP Lambert","year":"2007","unstructured":"Lambert, M. P., Sachais, B. S. & Kowalska, M. A. Chemokines and thrombogenicity. Thromb. Haemost. 97, 722\u2013729 (2007).","journal-title":"Thromb. Haemost."},{"key":"44779_CR60","first-page":"1","volume":"14","author":"MJ Iglesias","year":"2023","unstructured":"Iglesias, M. J. et al. Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism. Nat. Commun. 14, 1\u201323 (2023).","journal-title":"Nat. Commun."},{"key":"44779_CR61","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.it.2007.02.006","volume":"28","author":"MM Markiewski","year":"2007","unstructured":"Markiewski, M. M., Nilsson, B., Nilsson Ekdahl, K., Mollnes, T. E. & Lambris, J. D. Complement and coagulation: strangers or partners in crime? Trends Immunol. 28, 184\u2013192 (2007).","journal-title":"Trends Immunol."},{"key":"44779_CR62","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s40246-019-0199-1","volume":"13","author":"MS Saddala","year":"2019","unstructured":"Saddala, M. S. et al. Transcriptome-wide analysis of differentially expressed chemokine receptors, SNPs, and SSRs in the age-related macular degeneration. Hum. Genomics. 13, 15 (2019).","journal-title":"Hum. Genomics"},{"key":"44779_CR63","doi-asserted-by":"publisher","first-page":"534","DOI":"10.4049\/jimmunol.2000072","volume":"207","author":"F Gyapon-Quast","year":"2021","unstructured":"Gyapon-Quast, F. et al. Defining the Glycosaminoglycan Interactions of Complement Factor H\u2013Related Protein 5. J. Immunol. 207, 534\u2013541 (2021).","journal-title":"J. Immunol."},{"key":"44779_CR64","doi-asserted-by":"publisher","first-page":"2823","DOI":"10.1111\/bph.15290","volume":"178","author":"C Skerka","year":"2021","unstructured":"Skerka, C. et al. Factor H-related protein 1: a complement regulatory protein and guardian of necrotic-type surfaces. Br. J. Pharmacol. 178, 2823\u20132831 (2021).","journal-title":"Br. J. Pharmacol."},{"key":"44779_CR65","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.3389\/fimmu.2020.01297","volume":"11","author":"\u00c9 K\u00e1rp\u00e1ti","year":"2020","unstructured":"K\u00e1rp\u00e1ti, \u00c9. et al. Interaction of the Factor H Family Proteins FHR-1 and FHR-5 With DNA and Dead Cells: Implications for the Regulation of Complement Activation and Opsonization. Front. Immunol. 11, 1297 (2020).","journal-title":"Front. Immunol."},{"key":"44779_CR66","doi-asserted-by":"publisher","first-page":"8427","DOI":"10.1074\/jbc.M007994200","volume":"276","author":"J Hellwage","year":"2001","unstructured":"Hellwage, J. et al. The Complement Regulator Factor H Binds to the Surface Protein OspE of Borrelia burgdorferi. J. Biol. Chem. 276, 8427\u20138435 (2001).","journal-title":"J. Biol. Chem."},{"key":"44779_CR67","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.04008","author":"JJE Caesar","year":"2014","unstructured":"Caesar, J. J. E. et al. Competition between antagonistic complement factors for a single protein on N. meningitidis rules disease susceptibility. eLife https:\/\/doi.org\/10.7554\/eLife.04008 (2014).","journal-title":"eLife"},{"key":"44779_CR68","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.1001\/jama.286.19.2466","volume":"286","author":"LM Jampol","year":"2001","unstructured":"Jampol, L. M. & Ferris, F. L. Antioxidants and Zinc to Prevent Progression of Age-Related Macular Degeneration. JAMA 286, 2466\u20132468 (2001).","journal-title":"JAMA"},{"key":"44779_CR69","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1001\/archopht.119.10.1417","volume":"119","author":"A Kassoff","year":"2001","unstructured":"Kassoff, A. et al. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report 8. Arch. Ophthalmol. 119, 1417\u20131436 (2001).","journal-title":"Arch. Ophthalmol."},{"key":"44779_CR70","doi-asserted-by":"publisher","first-page":"e112682","DOI":"10.1371\/journal.pone.0112682","volume":"9","author":"D Smailhodzic","year":"2014","unstructured":"Smailhodzic, D. et al. Zinc Supplementation Inhibits Complement Activation in Age-Related Macular Degeneration. PLoS One. 9, e112682 (2014).","journal-title":"PLoS One"},{"key":"44779_CR71","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1016\/j.jmb.2011.03.006","volume":"408","author":"R Nan","year":"2011","unstructured":"Nan, R. et al. Zinc Binding to the Tyr402 and His402 Allotypes of Complement Factor H: Possible Implications for Age-Related Macular Degeneration. J. Mol. Biol. 408, 714\u2013735 (2011).","journal-title":"J. Mol. Biol."},{"key":"44779_CR72","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.imbio.2011.10.003","volume":"217","author":"SJ Perkins","year":"2012","unstructured":"Perkins, S. J., Nan, R., Li, K., Khan, S. & Miller, A. Complement Factor H\u2013ligand interactions: Self-association, multivalency and dissociation constants. Immunobiology 217, 281\u2013297 (2012).","journal-title":"Immunobiology"},{"key":"44779_CR73","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/S0899-9007(99)00148-3","volume":"15","author":"B Hennig","year":"1999","unstructured":"Hennig, B. et al. Zinc nutrition and apoptosis of vascular endothelial cells: implications in atherosclerosis. Nutrition 15, 744\u2013748 (1999).","journal-title":"Nutrition"},{"key":"44779_CR74","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1093\/jn\/122.6.1242","volume":"122","author":"B Hennig","year":"1992","unstructured":"Hennig, B., Wang, Y., Ramasamy, S. & McClain, C. J. Zinc deficiency alters barrier function of cultured porcine endothelial cells. J. Nutr. 122, 1242\u20131247 (1992).","journal-title":"J. Nutr."},{"key":"44779_CR75","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/j.redox.2014.06.011","volume":"2","author":"MM Cortese-Krott","year":"2014","unstructured":"Cortese-Krott, M. M. et al. Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Redox Biol. 2, 945\u2013954 (2014).","journal-title":"Redox Biol."},{"key":"44779_CR76","doi-asserted-by":"publisher","first-page":"7137","DOI":"10.4049\/jimmunol.210.Supp.71.37","volume":"210","author":"A Zarantonello","year":"2023","unstructured":"Zarantonello, A. et al. Intracellular complement proteins are tumor-promoting effectors and poor prognosis biomarkers in renal cancer. J. Immunol. 210, 7137\u20137137 (2023).","journal-title":"J. Immunol."},{"key":"44779_CR77","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1016\/j.immuni.2013.10.018","volume":"39","author":"MK Liszewski","year":"2013","unstructured":"Liszewski, M. K. et al. Intracellular complement activation sustains T Cell homeostasis and mediates effector differentiation. Immunity 39, 1143\u20131157 (2013).","journal-title":"Immunity"},{"key":"44779_CR78","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1042\/bj3260321","volume":"326","author":"J Hellwage","year":"1997","unstructured":"Hellwage, J., K\u00fchn, S. & Zipfel, P. F. The human complement regulatory factor-H-like protein 1, which represents a truncated form of factor H, displays cell-attachment activity. Biochem. J. 326, 321\u2013327 (1997).","journal-title":"Biochem. J."},{"key":"44779_CR79","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-021-93708-5","volume":"11","author":"R Choudhury","year":"2021","unstructured":"Choudhury, R. et al. FHL-1 interacts with human RPE cells through the \u03b15\u03b21 integrin and confers protection against oxidative stress. Sci. Rep. 11, 1\u201317 (2021).","journal-title":"Sci. Rep."},{"key":"44779_CR80","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1042\/bj2490593","volume":"249","author":"J Ripoche","year":"1988","unstructured":"Ripoche, J., Day, A. J., Harris, T. J. & Sim, R. B. The complete amino acid sequence of human complement factor H. Biochem. J. 249, 593\u2013602 (1988).","journal-title":"Biochem. J."},{"key":"44779_CR81","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1042\/bj2580927","volume":"258","author":"M Fontaine","year":"1989","unstructured":"Fontaine, M. et al. Truncated forms of human complement factor H. Biochem. J. 258, 927\u2013930 (1989).","journal-title":"Biochem. J."},{"key":"44779_CR82","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1093\/glycob\/cwm060","volume":"17","author":"F Fenaille","year":"2007","unstructured":"Fenaille, F. et al. Site-specific N-glycan characterization of human complement factor H. Glycobiology 17, 932\u2013944 (2007).","journal-title":"Glycobiology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44779-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44779-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44779-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T20:39:31Z","timestamp":1781642371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44779-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,22]]},"references-count":82,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["44779"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-44779-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,22]]},"assertion":[{"value":"23 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9651"}}