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Updated: Oct 17, 2026

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Published on: February 7, 2025
Lactate dehydrogenase A-dependent redox control of selective mRNA translation directs monocyte fate commitment
Ning Yang1, Huixia He1, Xin Liu1
1Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
Abstract:
Monocyte-to-macrophage differentiation is a central process that shapes immune responses across diverse contexts, yet how inflammatory cues engage metabolism to instruct monocyte fate commitment remains unclear. Here, using a CRISPR-based metabolic screen combined with monocyte-specific perturbations in bacterial lung infection, we identified lactate dehydrogenase A (LDHA) as a key metabolic regulator of monocyte commitment to the nitric oxide synthase 2 (NOS2)+ macrophage fate in vivo. LDHA-dependent cytosolic nicotinamide adenine dinucleotide (NAD+) regeneration enabled selective hypoxia-inducible factor 1-alpha (HIF1α) translation through its 5' untranslated region (UTR) and is associated with structural remodeling of this region. HIF1α then functioned as a downstream effector that promoted the NOS2+ macrophage fate. Granulocyte-macrophage colony-stimulating factor (GM-CSF) further acted as an upstream metabolic priming signal that enhanced LDHA-dependent HIF1α regulation and supported this differentiation process. Together, these findings suggest that metabolic redox state regulates monocyte fate commitment through selective mRNA translation coupled to RNA structural remodeling.
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