Wei Xuejiao, Long Mengtuan, Yu Jiayuan, Du Yujun
Department of Nephrology, the First Hospital of Jilin University, Changchun City, Jilin Province, China.
Laboratory of Cancer Precision Medicine, the First Hospital of Jilin University, Changchun City, Jilin Province, China.
Ann Med. 2025 Dec;57(1):2587326. doi: 10.1080/07853890.2025.2587326. Epub 2025 Nov 14.
Disturbances in energy metabolism are increasingly recognized as a key factor in the development of diabetic kidney disease (DKD). Among the pathological features of advanced DKD, renal fibrosis is both common and irreversible. With growing insight into metabolic reprogramming, lactate and its epigenetic derivative-lactylation-have gained attention as potential modulators of disease progression.
A systematic literature search was conducted in databases including PubMed, Embase, and Web of Science using keywords such as 'lactate', 'lactylation', 'diabetic kidney disease', 'renal fibrosis', and 'metabolic reprogramming'. Studies were included if they focused on the association between lactate/lactylation and DKD-related renal fibrosis, with priority given to preclinical (animal models, cell experiments) and clinical (human biopsy, cohort studies) evidence. Exclusion criteria were non-relevant studies, duplicates and articles with insufficient data.
In DKD, elevated lactate levels are associated with altered energy metabolism (enhanced glycolysis, impaired mitochondrial oxidative phosphorylation), inflammation activation (macrophage polarization, pro-inflammatory cytokine release), and excessive extracellular matrix deposition in renal tissues. Quantitatively, studies have shown that urinary lactate levels in DKD patients are 2.3-3.5 times higher than those in healthy controls, and lactate concentrations >2.5 mM can suppress mitochondrial oxidative phosphorylation in proximal tubular epithelial cells. Through lactylation modification, lactate regulates the activity of key molecules: histone lactylation (e.g. H3K14la) modulates the transcription of fibrosis-related genes, while non-histone lactylation (including PKM2, Fis1, Twist, Snail lactylation) affects glycolytic enzyme activity, mitochondrial function, and epithelial-mesenchymal transition, collectively contributing to renal fibrosis.
The lactate-lactylation axis is closely associated with renal fibrosis progression in DKD, and targeting this axis offers a promising therapeutic strategy to potentially slow fibrosis and preserve renal function in DKD. Consequently, inhibiting lactate dehydrogenase A, modulating monocarboxylate transporters, or targeting lactylation enzymes may provide novel treatment avenues. However, current evidence remains largely correlative, underscoring the need for large-scale cohort studies and early-phase clinical trials to validate its translational potential.
能量代谢紊乱日益被认为是糖尿病肾病（DKD）发展的关键因素。在晚期DKD的病理特征中，肾纤维化既常见又不可逆。随着对代谢重编程的深入了解，乳酸及其表观遗传衍生物——乳酰化——作为疾病进展的潜在调节因子受到关注。
在包括PubMed、Embase和Web of Science在内的数据库中进行系统的文献检索，使用“乳酸”、“乳酰化”、“糖尿病肾病”、“肾纤维化”和“代谢重编程”等关键词。如果研究聚焦于乳酸/乳酰化与DKD相关肾纤维化之间的关联，则纳入研究，优先考虑临床前（动物模型、细胞实验）和临床（人体活检、队列研究）证据。排除标准为不相关研究、重复研究和数据不足的文章。
在DKD中，乳酸水平升高与能量代谢改变（糖酵解增强、线粒体氧化磷酸化受损）、炎症激活（巨噬细胞极化、促炎细胞因子释放）以及肾组织中细胞外基质过度沉积有关。定量研究表明，DKD患者的尿乳酸水平比健康对照高2.3至3.5倍，且乳酸浓度>2.5 mM可抑制近端肾小管上皮细胞的线粒体氧化磷酸化。通过乳酰化修饰，乳酸调节关键分子的活性：组蛋白乳酰化（如H3K14la）调节纤维化相关基因的转录，而非组蛋白乳酰化（包括PKM2、Fis1、Twist、Snail乳酰化）影响糖酵解酶活性、线粒体功能和上皮-间质转化，共同导致肾纤维化。
乳酸-乳酰化轴与DKD中肾纤维化进展密切相关，针对该轴提供了一种有前景的治疗策略，有可能减缓纤维化并保留DKD患者的肾功能。因此，抑制乳酸脱氢酶A、调节单羧酸转运体或靶向乳酰化酶可能提供新的治疗途径。然而，目前的证据在很大程度上仍是相关性的，强调需要大规模队列研究和早期临床试验来验证其转化潜力。
