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Whether H<jats:sub>2<\/jats:sub>S is involved in the regulation of erythrocyte functions remains unknown. Using mice with a genetic deficiency in a H<jats:sub>2<\/jats:sub>S natural synthesis enzyme cystathionine\u2010<jats:italic>\u03b3<\/jats:italic>\u2010lyase (CSE) and high\u2010throughput metabolomic profiling, we found that levels of erythrocyte 2,3\u2010bisphosphoglycerate (2,3\u2010BPG), an erythroid\u2010specific metabolite negatively regulating hemoglobin\u2010 (Hb\u2010) oxygen (O<jats:sub>2<\/jats:sub>) binding affinity, were increased in CSE knockout (<jats:italic>Cse<\/jats:italic><jats:sup>-\/-<\/jats:sup>) mice under normoxia. Consistently, the 50% oxygen saturation (P50) value was increased in erythrocytes of <jats:italic>Cse<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice. These effects were reversed by treatment with H<jats:sub>2<\/jats:sub>S donor GYY4137. In the models of cultured mouse and human erythrocytes, we found that H<jats:sub>2<\/jats:sub>S directly acts on erythrocytes to decrease 2,3\u2010BPG production, thereby enhancing Hb\u2010O<jats:sub>2<\/jats:sub> binding affinity. Mouse genetic studies showed that H<jats:sub>2<\/jats:sub>S produced by peripheral tissues has a tonic inhibitory effect on 2,3\u2010BPG production and consequently maintains Hb\u2010O<jats:sub>2<\/jats:sub> binding affinity in erythrocytes. We further revealed that H<jats:sub>2<\/jats:sub>S promotes Hb release from the membrane to the cytosol and consequently enhances bisphosphoglycerate mutase (BPGM) anchoring to the membrane. These processes might be associated with S\u2010sulfhydration of Hb. Moreover, hypoxia decreased the circulatory H<jats:sub>2<\/jats:sub>S level and increased the erythrocyte 2,3\u2010BPG content in mice, which could be reversed by GYY4137 treatment. Altogether, our study revealed a novel signaling pathway that regulates oxygen\u2010carrying capacity in erythrocytes and highlights a previously unrecognized role of H<jats:sub>2<\/jats:sub>S in erythrocyte 2,3\u2010BPG production.<\/jats:p>","DOI":"10.1155\/2021\/8877691","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T05:11:17Z","timestamp":1613279477000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Hydrogen Sulfide Is a Regulator of Hemoglobin Oxygen\u2010Carrying Capacity via Controlling 2,3\u2010BPG Production in 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