Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by accelerated platelet destruction and impaired platelet production [1]. Although multiple therapies are available, some patients experience relapse, limited treatment durability, or treatment-related infections. The team previously showed that CD38-targeted therapy can induce rapid platelet recovery in refractory ITP, suggesting a mechanism beyond depletion of antibody-producing cells [2–4]. Given the emerging role of immunometabolism in shaping immune-cell function, the researchers investigated whether the CD38–NAD⁺ axis regulates macrophage-mediated platelet clearance and whether restoring NAD⁺ could provide a non-cell-depleting therapeutic strategy for ITP.

On April 29, 2026, the team led by Lei Zhang, Renchi Yang, and Jun Wei from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, reported their findings online in Nature Medicine (IF = 50.0) in an article entitled “Low-dose oral nicotinamide mononucleotide for immune thrombocytopenia: a phase 1/2 trial.” The study identified the CD38–NAD⁺ axis as a key regulator of macrophage-mediated platelet clearance in ITP. Restoring NAD⁺ with β-nicotinamide mononucleotide (NMN) suppressed pro-inflammatory macrophage activity and platelet phagocytosis, while low-dose oral NMN showed a favorable safety profile and preliminary clinical activity.

Building on the rapid platelet recovery observed with anti-CD38 therapy, the team used complementary mouse models and mechanistic studies to show that CD38 promotes antibody-mediated platelet clearance by regulating macrophage function. Mechanistically, CD38-driven NAD⁺ depletion promoted a pro-inflammatory macrophage state, increased FcγRI expression, and enhanced the phagocytosis of antibody-opsonized platelets. Restoring NAD⁺ with NMN suppressed NF-κB signaling and NLRP3 inflammasome activation, reduced platelet phagocytosis, and ameliorated thrombocytopenia without substantially affecting humoral immunity.

The team further validated these findings in macrophages derived from patients with ITP, where NMN reduced FcγRI expression and platelet phagocytosis. Based on these results, a single-arm, open-label phase 1/2 trial was conducted in 25 adults with ITP receiving low-dose oral NMN. NMN was well tolerated, with no treatment-related serious adverse events, and five patients met the primary platelet response endpoint. By week 8, 52% of patients showed a partial or suboptimal platelet response.

This study establishes the CD38–NAD⁺ axis as an important regulator of macrophage-mediated platelet clearance in ITP and provides proof of concept for a non-cell-depleting immunometabolic therapeutic strategy based on NAD⁺ restoration. By linking a clinical observation to mechanistic discovery and back to clinical translation, the work exemplifies an integrated bedside-to-bench-to-bedside research pathway.These findings support further exploration of immunometabolic approaches that suppress pathogenic immune functions while preserving humoral immunity in ITP and other autoantibody-mediated diseases.

This study was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the Tianjin Science and Technology Program, and the Tianjin Young Investigator Program (Category A; formerly the Distinguished Young Scholars Fund), among other funding sources. Lei Zhang and Jun Wei served as co-corresponding authors. Huiyuan Li, Yuan Xu, Yunfei Chen, Lulu Ji, and Yanmei Xu contributed equally as co-first authors.

Link: https://www.nature.com/articles/s41591-026-04366-x

References:

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