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However, clinical application of recombinant TRX (rhTRX) is constrained by rapid clearance and proliferative intracellular activity. To overcome these limitations, a rationally designed TRX variant, ORP100S, was engineered for enhanced stability, prolonged extracellular target engagement, and improved protective function, with development of novel single\u2010turnover insulin reduction and hybrid\u2010immunocapture LC\u2010MS assays. ORP100S demonstrates high\u2010yield expression in\n                    <jats:italic>E. coli<\/jats:italic>\n                    (16\u00a0g\u00a0L\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) and exhibits significant in vivo mitigating effects when administered subcutaneously to rodents and non\u2010human primates exposed to otherwise\u2010lethal total\u2010body ionizing radiation. Compared to native TRX, ORP100S displays improved pharmacokinetic and pharmacodynamic properties without promoting murine or human cancer cell proliferation. Additionally, ORP100S protects hematopoietic stem\/progenitor cells (HSPCs) from chemotherapy\u2010induced toxicity in vitro and in vivo synergistically with co\u2010administered granulocyte\u2010macrophage colony\u2010stimulating factor (GM\u2010CSF). Mechanistic studies revealed that ORP100S modulates the Kruppel\u2010like factor 4 (KLF4)\u2010p53 pathway to selectively inhibit ferroptosis in HSPCs but not cancer cells. These findings highlight the potential of ORP100S as a novel therapeutic agent for mitigating acute radiation injury and improving the safety and efficacy of chemotherapy without compromising antitumor activity.\n                  <\/jats:p>","DOI":"10.1002\/advs.202504426","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T15:01:33Z","timestamp":1757602893000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimized Monothiol Thioredoxin Derivative (ORP100S) Protects In Vitro and In Vivo from Radiation and Chemotoxicity Without Promoting Tumor Proliferation"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-9917","authenticated-orcid":false,"given":"Jian","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy Department of Medicine Duke University Medical Center  Durham NC 27710 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobei","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy Department of Medicine Duke University Medical Center  Durham NC 27710 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parker","family":"Mathews","sequence":"additional","affiliation":[{"name":"School of Medicine Duke University  Durham NC 27710 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaima","family":"Jabbar","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy Department of Medicine Duke University Medical Center  Durham NC 27710 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy Department of Medicine Duke University Medical Center  Durham NC 27710 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haim","family":"Moskowitz","sequence":"additional","affiliation":[{"name":"OrPro Therapeutics, Inc  San Diego CA 92130 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Duan","sequence":"additional","affiliation":[{"name":"OrPro Therapeutics, Inc  San Diego CA 92130 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David P.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Pediatrics National Jewish Health  Denver CO 80206 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George William","family":"Schaaf","sequence":"additional","affiliation":[{"name":"Wake Forest School of Medicine  Winston\u2010Salem NC 27157 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John D.","family":"Olson","sequence":"additional","affiliation":[{"name":"Wake Forest School of Medicine  Winston\u2010Salem NC 27157 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew N.","family":"Macintyre","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute DUMC Box 103020 Duke University  Durham NC 27710 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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