PKM2: A gatekeeper in macrophage metabolic reprogramming

Metabolic reprogramming serves as a core adaptive mechanism for cells to respond to microenvironmental changes and plays a decisive role in macrophage functional polarization. Pyruvate kinase M2 (PKM2), recognized for its dynamic allosteric regulation, acts as a critical molecular hub linking metabolic reprogramming with immune responses. Despite numerous studies affirming the pivotal role of PKM2 in tumor metabolism, its complex regulatory mechanisms within the immune metabolic network remain inadequately defined, significantly hindering the advancement of targeted therapeutic strategies for metabolic reprogramming. This review meticulously analyzes and highlights the significance of PKM2-mediated metabolic reprogramming in macrophages across several organ disorders. We subsequently examined various PKM2 inhibitors and activators, along with natural compounds that modulate PKM2, as research evidence for therapeutic approaches to diseases, particularly with the metabolic reprogramming of macrophages. This study comprehensively examines the theoretical foundation, research evidence, and intervention strategies regarding PKM2 as a crucial regulatory element of macrophages, offering novel perspectives on therapeutic approaches for macrophage metabolic reprogramming. ● Propose multi-level evidence for PKM2 as a key regulatory factor in macrophage glucose metabolism reprogramming. ● Analyze the regulatory mechanism of the dynamic equilibrium of PKM2 conformation. ● Map the cross-tissue disease spectrum of PKM2-mediated macrophage metabolic reprogramming. ● Evaluate the efficacy of chemical/natural modulators targeting PKM2. ● Propose the future development of intervention methods targeting PKM2 to regulate macrophage metabolic reprogramming.