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Reshaping glycometabolic reprogramming to suppress M1 macrophage polarization for diabetic wound therapy

XIANG Yue-Yu¹, ZHENG Ai-Tian², WU Biao-Liang^2,*

¹Graduate School of Youjiang Medical University for Nationalities, Baise 533000, China；²Department of Endocrinology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China

Abstract

Diabetic chronic wounds, a severe diabetic complication, are closely linked to macrophage metabolic reprogramming. Under hyperglycemic conditions, macrophage metabolism shifts from oxidative phosphorylation to aerobic glycolysis, triggering increased lactate production, activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, and imbalance in macrophage polarization, ultimately leading to difficult wound healing. Metabolic imbalance also results in an altered wound microenvironment characterized by inhibited angiogenesis, aberrant matrix remodeling, and compromised stem cell function. Key metabolites like lactate and pyruvate exacerbate oxidative stress and epigenetic disruption via receptor-mediated signals or chromatin modifications, creating a "metabolism-inflammation" vicious cycle. Metabolism-based therapeutic strategies for diabetic wounds include: 1) targeting lactate dehydrogenase A (LDHA) to inhibit lactate production; 2) modulating monocarboxylate transporter (MCT) to maintain intracellular pH homeostasis; 3) stabilizing pyruvate kinase M2 (PKM2) tetramers to restore pyruvate metabolism; 4) applying mitochondria-targeted antioxidants to intervene in oxidative stress; and 5) utilizing specific small molecule inhibitors (including dichloroacetate as a pyruvate dehydrogenase kinase 4 inhibitor, dimethyl malonate as a succinate dehydrogenase inhibitor, and tanshinone IIA). These strategies provide novel approaches for restoring metabolic-immune balance.

Key words: diabetic chronic wounds; macrophage polarization; glucose metabolism reprogramming; glycolysis; oxidative stress; targeted therapy

Received: 　　Accepted:

Corresponding author: 吴标良　　E-mail:

DOI: 10.13294/j.aps.2026.0047

Citing This Article：

XIANG Yue-Yu, ZHENG Ai-Tian, WU Biao-Liang. Reshaping glycometabolic reprogramming to suppress M1 macrophage polarization for diabetic wound therapy. Acta Physiol Sin 2026; 78 (3): 487-500 (in Chinese with English abstract).