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Among GAG derivatives, 2-O, 3-O desulfated heparin (ODSH) is a chemically modified heparin derivative characterized by markedly reduced anticoagulant activity yet preserved affinity for key inflammatory mediators. This review summarizes current knowledge on ODSH structure\u2013function relationships, molecular mechanisms, and therapeutic applications across inflammatory, vascular, and immune-mediated diseases. ODSH modulates several convergent pathogenic processes, including HMGB1-RAGE\/TLR4 signaling, neutrophil elastase-mediated tissue injury, PF4-dependent platelet activation, selectin-mediated adhesion, and thrombin-induced endothelial permeability. These actions arise from both direct molecular interactions and indirect sequestration of extracellular mediators, collectively associated with reduced cytokine release, enhanced endothelial barrier stability, and attenuation of inflammation\u2013coagulation crosstalk. Preclinical studies report protective effects in acute lung injury, cystic fibrosis, ischemia\u2013reperfusion injury, traumatic brain injury, thrombocytopenia, and metastatic cancer. Some pilot clinical observations in acute myeloid leukemia and septic peritonitis have reported favorable biological effects. Despite multimodal activity, limitations include incomplete pharmacokinetic characterization, limited comparative studies with other desulfated heparins, and the need for dose\u2013response and safety evaluation in human trials. Overall, available evidence suggests that ODSH may have therapeutic relevance in diseases characterized by excessive inflammation, endothelial dysfunction, and dysregulated host responses. This review integrates current evidence to guide future mechanistic and translational investigation into ODSH and related low-anticoagulant heparin derivatives.<\/jats:p>","DOI":"10.3390\/antiox15091179","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:03:17Z","timestamp":1789632197000},"page":"1179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Emerging Role, Molecular Mechanisms, and Therapeutic Potential of 2-O, 3-O Desulfated Heparin (ODSH) Across Inflammatory and Vascular Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2447-2355","authenticated-orcid":false,"given":"Rahul S.","family":"Patil","sequence":"first","affiliation":[{"name":"Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5960-4433","authenticated-orcid":false,"given":"Shweta R.","family":"Patil","sequence":"additional","affiliation":[{"name":"Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce N.","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0627-7185","authenticated-orcid":false,"given":"Alexander D.","family":"Verin","sequence":"additional","affiliation":[{"name":"Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0022-3565(24)36816-8","article-title":"Selective O-desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung","volume":"282","author":"Fryer","year":"1997","journal-title":"J. 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