{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:13:15Z","timestamp":1791144795473,"version":"4.1.0"},"reference-count":59,"publisher":"American Society of Hematology","issue":"8","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,4,23]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sickle cell disease (SCD) is an autosomal-recessive hemolytic disorder with high morbidity and mortality. The pathophysiology of SCD is characterized by the polymerization of deoxygenated intracellular sickle hemoglobin, which causes the sickling of erythrocytes. The recent development of metabolomics, the newest member of the \u201comics\u201d family, has provided a powerful new research strategy to accurately measure functional phenotypes that are the net result of genomic, transcriptomic, and proteomic changes. Metabolomics changes respond faster to external stimuli than any other \u201come\u201d and are especially appropriate for surveilling the metabolic profile of erythrocytes. In this review, we summarize recent pioneering research that exploited cutting-edge metabolomics and state-of-the-art isotopically labeled nutrient flux analysis to monitor and trace intracellular metabolism in SCD mice and humans. Genetic, structural, biochemical, and molecular studies in mice and humans demonstrate unrecognized intracellular signaling pathways, including purinergic and sphingolipid signaling networks that promote hypoxic metabolic reprogramming by channeling glucose metabolism to glycolysis via the pentose phosphate pathway. In turn, this hypoxic metabolic reprogramming induces 2,3-bisphosphoglycerate production, deoxygenation of sickle hemoglobin, polymerization, and sickling. Additionally, we review the detrimental role of an impaired Lands\u2019 cycle, which contributes to sickling, inflammation, and disease progression. Thus, metabolomic profiling allows us to identify the pathological role of adenosine signaling and S1P-mediated erythrocyte hypoxic metabolic reprogramming and hypoxia-induced impaired Lands' cycle in SCD. These findings further reveal that the inhibition of adenosine and S1P signaling cascade and the restoration of an imbalanced Lands' cycle have potent preclinical efficacy in counteracting sickling, inflammation, and disease progression.<\/jats:p>","DOI":"10.1182\/bloodadvances.2018030619","type":"journal-article","created":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T20:54:21Z","timestamp":1556052861000},"page":"1347-1355","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":45,"title":["Metabolomic and molecular insights into sickle cell disease and innovative therapies"],"prefix":"10.1182","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3565-4509","authenticated-orcid":false,"given":"Morayo G.","family":"Adebiyi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School, Houston, TX; and"},{"name":"University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7289-8102","authenticated-orcid":false,"given":"Jeanne M.","family":"Manalo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School, Houston, TX; and"},{"name":"University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School, Houston, TX; and"},{"name":"University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2019,4,23]]},"reference":[{"issue":"3","key":"2020021109193616400_B1","first-page":"179","article-title":"Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910","volume":"74","author":"Herrick","year":"2001","journal-title":"Yale J Biol Med"},{"key":"2020021109193616400_B2","first-page":"334","article-title":"Molecular disease and evolution","volume":"40","author":"Pauling","year":"1964","journal-title":"Bull N Y Acad Med"},{"issue":"2865","key":"2020021109193616400_B3","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1126\/science.110.2865.543","article-title":"Sickle cell anemia a molecular disease","volume":"110","author":"Pauling","year":"1949","journal-title":"Science"},{"issue":"1","key":"2020021109193616400_B4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0021-9258(18)56146-9","article-title":"Ratio of sickle-cell anemia hemoglobin to normal hemoglobin in sicklemics","volume":"188","author":"Wells","year":"1951","journal-title":"J Biol Chem"},{"issue":"1-3","key":"2020021109193616400_B5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0301-4622(02)00269-7","article-title":"Linus Pauling and sickle cell disease","volume":"100","author":"Eaton","year":"2003","journal-title":"Biophys Chem"},{"issue":"2","key":"2020021109193616400_B6","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/0006-3002(59)90183-0","article-title":"Abnormal human haemoglobins. 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