Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

Tet2 clonal hematopoiesis in Ldlr−/− mice impairs macrophage efferocytosis and glycolysis-lactate-actin polymerization, preventing significant necrotic core reduction and fibrous cap thickening during LDL lowering.

• Why it matters: CH from TET2 mutations is linked to higher atherosclerotic risk, but whether it blocks clinically relevant plaque regression during LDL lowering is unclear.
• What they did: Mice with conditional Tet2 deletion in hematopoietic stem cells were studied after 12 weeks of Western diet, then subjected to LDL lowering with either continued Western diet or lipid normalization; efferocytosis and single-cell RNA-seq showed glycolysis and phagocytosis defects, rescued by lactate or molidustat.
• The result: Tet2-deficient monocyte/macrophage populations showed defective glycolysis, phagocytosis, and actin polymerization, with efferocytosis defects sustained in macrophage models; lactate supplementation or molidustat reversed necrotic core and fibrous cap remodeling during LDL lowering, and reduced plasma lactate was observed in UK Biobank TET2 clonal hematopoiesis carriers.

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