Mechanisms of Macrophage Glycolytic Reprogramming and Interventional Effects of Traditional Chinese Medicine on Renal Fibrosis

Abstract

Abstract Renal fibrosis (RF) is a common pathological outcome of multiple chronic kidney diseases (CKDs), accompanied by substantial extracellular matrix (ECM) deposition and gradual decline of renal function. To date, no clinically viable treatment can reverse progressive renal fibrosis, making it critical to uncover its pathogenic mechanisms. Macrophages display remarkable phenotypic heterogeneity in fibrotic kidneys. Dramatic metabolic reprogramming occurs in these immune cells, with elevated aerobic glycolysis serving as a dominant trait. This metabolic switch not only sustains the energy demand of activated macrophages but also promotes the formation of pro-inflammatory and pro-fibrotic phenotypes. Apart from glycolysis, dysregulated glutaminolysis and lipid metabolism also interact with glycolysis to aggravate renal damage. TCM, owing to its multi-component and multi-target advantages, has shown favorable preclinical effects against renal fibrosis. A growing body of evidence suggests that TCM-derived monomers, formulas, and extracts may exert anti-fibrotic actions by modulating macrophage glycolytic reprogramming. However, the field faces prominent challenges. All relevant data are limited to preclinical studies, with no clinical validation to date. Most research evaluates glycolytic activity indirectly via the expression of metabolic enzymes rather than direct metabolic flux measurement. Additionally, the pharmacokinetics, toxicity, and translational potential of TCM components remain inadequately characterized. This narrative review elaborates the molecular mechanisms of macrophage glycolytic reprogramming in renal fibrosis and summarizes preclinical research on TCM interventions, while clarifying current research deficiencies and future directions.