G6PD suppresses thrombopoiesis via interfering with TMOD3-mediated actin dynamics.

Glucose-6-phosphate dehydrogenase (G6PD), the committed enzyme of the pentose phosphate pathway, plays a pivotal role in glucose metabolism, which is integral to platelet biology. Although G6PD deficiency is a prevalent enzyme defect worldwide, the specific role of G6PD itself in platelets remains unclear. Herein, we discover a previously unrecognized phenotype in both human patients and murine models, demonstrating that G6PD deficiency leads to elevated platelet counts through enhanced proplatelet formation (PPF). Mechanistically, we reveal a non-canonical function of G6PD in regulating actin dynamics via its interaction with an actin-binding protein, tropomodulin-3 (TMOD3). The G6PD-TMOD3 interaction, which is concentration-dependently enhanced by nicotinamide adenine dinucleotide phosphate (NADP+), can limit actin rearrangement, thereby inhibiting PPF. Furthermore, we develop a G6PD-derived peptide, GC2P2, which potentiates the G6PD-TMOD3 interaction and significantly suppresses thrombocytopoiesis both in vitro and in vivo. In conclusion, our findings suggest that G6PD deficiency facilitates platelet biogenesis by altering TMOD3-mediated actin dynamics. The study provides new insights into thrombopoiesis and offers potential strategies for modulating platelet production.