{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T07:55:35Z","timestamp":1790582135637,"version":"4.1.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Transplant."],"abstract":"<jats:p>\n                    Recent advances in genetic engineering have substantially reduced the major carbohydrate barriers to pig-to-human xenotransplantation. Deletion of GGTA1, CMAH, and B4GALNT2 decreases\n                    <jats:italic>\u03b1<\/jats:italic>\n                    Gal, Neu5Gc, and B4GALNT2-dependent Sda-like xenoantigens and thereby attenuates preformed antibody binding and complement-mediated injury. However, removal of these major xenoantigens does not necessarily generate a human-compatible cell-surface glycome. In particular, CMAH knockout eliminates Neu5Gc but leaves a Neu5Ac-dominant sialome whose linkage, chemical modification, glycoconjugate carrier, density, and spatial presentation are not necessarily human-like. This review examines sialylation and glycan-dependent recognition as an underappreciated regulatory layer linking innate immunity, blood-cell homeostasis, complement regulation, and thromboinflammation in xenotransplantation. Two conceptual distinctions are emphasized. First, the direction and evidence depth of glycan\u2013receptor recognition must be explicitly considered. The best-established Siglec-1-dependent xenogeneic interaction is a graft-versus-host pathway, in which donor porcine Siglec-1-positive macrophages capture recipient human erythrocytes. Conversely, direct receptor-level binding of human Siglec-1 to CMAH-deficient gene-edited pig erythrocytes has recently been demonstrated, providing evidence for the reciprocal host-versus-graft direction; however, whether this interaction drives recipient macrophage phagocytosis or\n                    <jats:italic>in vivo<\/jats:italic>\n                    clearance remains unresolved. Donor ASGR1-dependent uptake of human platelets provides another direct example of glycan-dependent recipient blood-cell clearance. Second,\n                    <jats:italic>\u03b1<\/jats:italic>\n                    2,3-linked Neu5Ac illustrates a fundamental functional trade-off in sialome engineering. Neu5Ac\n                    <jats:italic>\u03b1<\/jats:italic>\n                    2,3Gal-containing glycans can serve as preferred ligands for Siglec-1-mediated capture, whereas\n                    <jats:italic>\u03b1<\/jats:italic>\n                    2,3-linked sialoglycans also contribute to Factor H-dependent recognition of self-associated surfaces and alternative complement regulation. Conversely, increasing\n                    <jats:italic>\u03b1<\/jats:italic>\n                    2,6-linked sialylation may reduce macrophage xenoreactivity and enhance inhibitory Siglec engagement but decrease\n                    <jats:italic>\u03b1<\/jats:italic>\n                    2,3-dependent Factor H recognition; thus, ST6GAL1 engineering should not be considered uniformly protective or equivalent to glycan \u201chumanization\u201d. Other pathways, including CD24\u2013Siglec-10 signaling, Siglec-9-mediated regulation of neutrophil activation and NETosis, and platelet Siglec signaling, provide additional mechanistic frameworks but remain incompletely validated in solid-organ xenotransplantation. We therefore propose that post-editing glycan compatibility should be evaluated according to receptor directionality, evidence depth, and functional trade-offs, rather than glycan abundance or donor genotype alone. Organ-, cell-, carrier-, and receptor-specific analyses integrating quantitative glycomics\/glycoproteomics, human receptor and immune-cell assays, functional crossmatching, and\n                    <jats:italic>ex vivo<\/jats:italic>\n                    perfusion are needed to link donor genotype to post-editing glycan phenotype and guide precision optimization of xenograft compatibility.\n                  <\/jats:p>","DOI":"10.3389\/frtra.2026.1968710","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T07:03:41Z","timestamp":1790579021000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neu5Gc and beyond: sialylation at the innate immune and thromboinflammatory interface of xenotransplantation"],"prefix":"10.3389","volume":"5","author":[{"given":"Jae Young","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Life Science, Gachon University","place":["Seongnam, Kyeonggi-Do, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1002\/path.4635","article-title":"The role of genetically engineered pigs in xenotransplantation research","volume":"238","author":"Cooper","year":"2016","journal-title":"J Pathol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1126\/science.aad1191","article-title":"Genome-wide inactivation of porcine endogenous retroviruses (PERVs)","volume":"350","author":"Yang","year":"2015","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1126\/science.1078942","article-title":"Production of \u03b11,3-galactosyltransferase-deficient 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