Nr-CWS regulates METTL3-mediated m6A modification of CDS2 mRNA in vascular endothelial cells and has prognostic significance.

Metabolic memory (MM) is a crucial factor in the delayed wound healing observed in diabetic patients. Although Nocardia rubrum cell wall skeleton (Nr-CWS) is used to promote macrophage proliferation in immune diseases, its impact on MM wounds in diabetes is unclear. This study reveals that transient hyperglycemia causes sustained damage to vascular endothelial cells by reducing METTL3 expression, leading to decreased RNA methylation and impaired cellular metabolism. Remarkably, Nr-CWS application increases METTL3 levels in these cells, facilitating the recovery of cell function. Further in vivo and in vitro analyses demonstrate that transient hyperglycemia-induced reduction in METTL3 hinders RNA methylation of the downstream gene CDS2, impacting mitochondrial function and energy metabolism and consequently reducing angiogenic capacity in endothelial cells. This impairment significantly influences diabetic wound healing. Our findings highlight the profound impact of transient hyperglycemia on wound healing, establishing METTL3 as a key player in vascular complications of diabetes. This study not only elucidates the pathophysiological mechanisms behind MM in diabetic wounds but also suggests Nr-CWS as a potential therapeutic agent, offering a novel approach for treating diabetic wounds.

代谢记忆（Metabolic memory，MM）是糖尿病患者出现伤口愈合延迟的关键影响因素。尽管红诺卡氏菌细胞壁骨架（Nocardia rubrum cell wall skeleton，Nr-CWS）常被用于促进免疫疾病中的巨噬细胞增殖，但其对糖尿病合并代谢记忆伤口的影响尚不明确。本研究揭示，一过性高血糖可通过降低METTL3的表达，对血管内皮细胞造成持续性损伤，进而导致RNA甲基化水平下降及细胞代谢功能受损。值得注意的是，Nr-CWS的应用可提升这些细胞内的METTL3水平，促进细胞功能恢复。进一步的体内外实验分析表明，一过性高血糖诱导的METTL3表达降低会阻碍下游基因CDS2的RNA甲基化，影响线粒体功能与能量代谢，进而降低内皮细胞的血管生成能力，这一损伤显著影响糖尿病伤口愈合。本研究结果揭示了一过性高血糖对伤口愈合的深远影响，确立了METTL3在糖尿病血管并发症中的关键作用。本研究不仅阐明了糖尿病伤口中代谢记忆的病理生理机制，还提出Nr-CWS可作为潜在治疗制剂，为糖尿病伤口的治疗提供了全新策略。