Protein phosphatase 2A orchestrates hematopoietic fate determination via modulation of lactate metabolism

Abnormal hematopoiesis is inherently linked to metabolic reprogramming. Protein phosphatase 2A (PP2A), a master regulator of hematopoietic homeostasis, has been implicated in multiple hematological disorders. However, the precise mechanisms by which PP2A coordinates metabolic networks to govern hematopoietic fate decisions remain poorly defined. Herein, we identify lactate as a critical mediator of myeloid-biased differentiation triggered by PP2A inactivation. Genetic ablation of PPP2CA, the catalytic subunit of PP2A, results in aberrant myeloid proliferation and lymphoid depletion. Transcriptomic profiling reveals that Ppp2ca deficiency alters the expression of transcriptional regulators governing hematopoietic lineage commitment and energy metabolism. Metabolomic analyses further demonstrate enhanced lactate metabolism in Ppp2ca-deficient hematopoietic progenitors. Importantly, either haploinsufficiency or pharmacological inhibition of lactate dehydrogenase A (LDHA) in vivo effectively reverses the abnormal hematopoiesis induced by Ppp2ca deficiency. Mechanistically, Ppp2ca deletion directly promotes the transcriptional initiation of glycolytic genes (e.g., Ldha) via RNA polymerase II (Pol II). This leads to heightened lactylation of histone deacetylases (HDACs) at specific residues-lysine 412 in HDAC1 and lysine 451 in HDAC2-impairing the assembly of the HDAC1/2/SIN3A co-repressor complex on chromatin, enhancing histone acetylation, and ultimately dysregulating hematopoietic gene expression. Collectively, our work establishes the "PP2A-Lactate-HDAC lactylation" axis as a pivotal regulator of hematopoiesis and identifies LDHA as a promising therapeutic target for PP2A-associated hematological disorders.