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重塑糖代谢重编程抑制M1型巨噬细胞极化治疗糖尿病创面

向玥腴¹, 郑爱甜², 吴标^2,*

¹右江民族医学院研究生学院，百色 533000；²右江民族医学院附属医院内分泌科，百色 533000

摘要

糖尿病慢性创面是糖尿病的严重并发症，其愈合障碍与巨噬细胞糖代谢重编程密切相关。在高血糖环境下，巨噬细胞代谢从氧化磷酸化转向有氧糖酵解，引发乳酸生成增加、核苷酸结合寡聚化结构域样受体蛋白

糖尿病慢性创面是糖尿病的严重并发症，其愈合障碍与巨噬细胞糖代谢重编程密切相关。在高血糖环境下，巨噬细胞代谢从氧化磷酸化转向有氧糖酵解，引发乳酸生成增加、核苷酸结合寡聚化结构域样受体蛋白3 (nucleotide-bindingoligomerization domain-like receptor protein 3, NLRP3)炎症小体活化及巨噬细胞极化失衡，进而导致创面难以愈合。代谢失衡引发创面微环境出现血管新生抑制、基质重塑异常、干细胞功能受损等特征。乳酸、丙酮酸等关键代谢物通过受体介导信号或染色质修饰加剧氧化应激和表观遗传失调，形成“代谢-炎症”恶性循环。基于代谢调控治疗糖尿病创面的策略包括：1)靶向乳酸脱氢酶A (lactate dehydrogenase A, LDHA)抑制乳酸生成；2)调节单羧酸转运蛋白(monocarboxylate transporter,MCT)维持细胞内pH稳态；3)稳定丙酮酸激酶M2 (pyruvate kinase M2, PKM2)四聚体以恢复丙酮酸代谢；4)应用线粒体靶向抗氧化剂干预氧化应激；以及5)使用特定小分子抑制剂(包括丙酮酸脱氢酶激酶4 抑制剂二氯乙酸、琥珀酸脱氢酶抑制剂丙二酸二甲酯和丹参酮IIA)，这些策略为恢复代谢-免疫平衡提供了新方向。

关键词： 糖尿病慢性创面; 巨噬细胞极化; 糖代谢重编程; 糖酵解; 氧化应激; 靶向治疗

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

收稿日期：　　录用日期：

通讯作者：吴标　　E-mail:

DOI: 10.13294/j.aps.2026.0047

引用本文：

向玥腴, 郑爱甜, 吴标. 重塑糖代谢重编程抑制M1型巨噬细胞极化治疗糖尿病创面[J]. 生理学报 2026; 78 (3): 487-500.

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).