GDF15 Ameliorates Deoxynivalenol-Induced Anemia by Resolving Ribosomal Stress-Mediated Erythropoietic Arrest.

Abstract

Deoxynivalenol (DON) is a prevalent trichothecene mycotoxin that contaminates global food supplies, posing significant health risks; however, targeted therapies against DON are scarce. Although DON-induced anemia is well-documented, the underlying mechanisms remain unclear. In this study, the effects of DON on erythropoiesis are examined in detail using complementary murine models and human primary erythroid cultures. DON impaired erythropoiesis by disrupting hematopoietic homeostasis as well as erythroid commitment and differentiation via ribosomal stress-mediated cell cycle arrest. Multi-omics analyses revealed that the effects of DON are attributed to ribosomal dysfunction, which selectively disrupted protein synthesis without altering mRNA expression. Mechanistically, DON downregulated translation of growth differentiation factor 15 (GDF15) along with decreases in β-catenin, Myc, and p21. Importantly, GDF15 supplementation rescued DON-induced erythropoietic defects in vitro and in vivo, restored levels of β-catenin, Myc, and p21, and cell cycle progression, indicating DON inhibits erythropoiesis via the GDF15-β-catenin-Myc-p21 axis. These findings elucidate the pathogenesis of DON-induced anemia and identify GDF15 as a novel therapeutic target against mycotoxin poisoning.