Low-dose oral nicotinamide mononucleotide for immune thrombocytopenia: a phase 1/2 trial

  • Nat Med. 2026 Jun;32(6):2026-2036. doi: 10.1038/s41591-026-04366-x.
Huiyuan Li  #  1  2 ,  Yuan Xu  #  1  2 ,  Yunfei Chen  #  1  2 ,  Lulu Ji  #  1  2 ,  Yanmei Xu  #  1  2 ,  Wenting Zheng  1  2 ,  Ting Sun  1  2 ,  Rongfeng Fu  1  2 ,  Xiaolei Pei  1  2 ,  Xiaofan Liu  1  2 ,  Feng Xue  1  2 ,  Wei Liu  1  2 ,  Wentian Wang  1  2 ,  Ying Chi  1  2 ,  Renchi Yang  1  2 ,  Jun Wei  3  4 ,  Lei Zhang  5  6
Affiliations
  • 1. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
  • 2. Tianjin Institutes of Health Science, Tianjin, China.
  • 3. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. [email protected].
  • 4. Tianjin Institutes of Health Science, Tianjin, China. [email protected].
  • 5. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. [email protected].
  • 6. Tianjin Institutes of Health Science, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 42056497 DOI: 10.1038/s41591-026-04366-x
Abstract

Autoimmunity remains challenging to treat without broad immunosuppression. We previously showed that anti-CD38 antibody can rapidly elevate platelet counts in refractory immune thrombocytopenia (ITP), but the underlying mechanism was unclear. Here we report that anti-CD38 antibody induces platelet recovery within 3 days, including after retreatment in relapsed cases. Mechanistically, CD38-mediated nicotinamide adenine dinucleotide (NAD+) depletion drives M1-like macrophage polarization with increased Fc gamma receptor I (FcγRI) expression, thereby promoting macrophage phagocytosis of opsonized platelets. In mice, CD38 inhibition or nicotinamide mononucleotide (NMN) supplementation restores NAD+, reprograms macrophages, downregulates FcγRI and prevents thrombocytopenia. In an ovalbumin immunization model, NMN treatment does not impair antigen-specific antibody production, supporting preservation of humoral responses. Based on these findings, we conducted a single-arm, open-label phase 1/2 trial of low-dose oral NMN (450 mg twice daily for 2 weeks) in adults with steroid-refractory or steroid-dependent ITP. Primary endpoints were safety/tolerability and platelet response (≥50 × 109 per liter within 2 weeks, confirmed by two consecutive measurements one or more days apart, without rescue therapy or dose escalation of Thrombopoietin Receptor agonists or corticosteroids). Among 25 enrolled patients, no dose-limiting toxicities or treatment-related serious adverse events occurred; NMN was well tolerated, with only mild treatment-related adverse events in 12% and non-severe infections (grade 1) in 8% of patients while immunoglobulin levels remained stable, consistent with preserved humoral immunity. Five patients (20.0%) met the primary platelet-response endpoint. In exploratory analyses, overall, 60% of patients achieved platelet counts more than 1.5× baseline during treatment, and 52% maintained responses through week 8. Together, these data identify the CD38-NAD+ axis as an immunometabolic checkpoint in ITP and support further exploration of NMN as a non-antibody-depleting metabolic strategy for antibody-mediated disease. ClinicalTrials.gov identifier: NCT06776510 .

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