Jul 2026· International Journal of General Medicine· Vol 19, pp. 1-24· 0 citations· 250 references
Medicine
TL;DR
A 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.
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.
This review systematically examines the mechanisms of metabolic reprogramming in different renal cell types and highlights their contribution to renal injury, highlighting the ability of natural products to confer renal protection by modulating key regulatory nodes of metabolic reprogramming.
Wenru Wang, Han Zhu, Keqin Zhao et al.· Journal of Translational Int...· 0 citations
Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive extracellular matrix deposition, tissue remodeling, and irreversible loss of lung function. Although inflammation contributes to disease progression, increasing evidence indicates that immunometabolic reprogramming is a central driver of fibrotic persistence. Alterations in glycolysis, mitochondrial function, lipid metabolism, and redox homeostasis actively regulate immune responses, fibroblast activation, and epithelial cell dysfunction, thereby sustaining a profibrotic microenvironment. This review synthesizes current advances in understanding how metabolic pathways regulate immune and structural cell behavior during pulmonary fibrosis. Particular emphasis is placed on metabolic checkpoints, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and nicotinamide adenine dinucleotide (NAD+)-dependent signaling, which integrate metabolic and inflammatory responses. We further discuss how mitochondrial dysfunction, hypoxia-inducible factor-1α (HIF-1α), reactive oxygen species (ROS), cellular senescence, and metabolic memory contribute to disease persistence. Emerging evidence supports metabolic crosstalk between immune cells and fibroblasts as a key mechanism driving fibrotic remodeling. Finally, we evaluate therapeutic strategies targeting immunometabolic pathways and discuss current translational challenges, including cellular heterogeneity, pathway redundancy, and limited clinical validation. Collectively, this review highlights immunometabolic regulation as a promising therapeutic framework and identifies opportunities for precision-based interventions in pulmonary fibrosis.
Hemraj Singh, Anushka Purwar, R. Taliyan· International Immunopharmaco...· 0 citations
Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized primarily by chronic inflammation of the synovial membrane and destruction of articular cartilage and bone. Previous research has predominantly focused on the abnormal activation of immune cells and the cascade of inflammatory cytokines. However, recent studies have reported that energy metabolism disorders, particularly glucose metabolism reprogramming, are closely associated with the pathogenesis of RA. Hypoxia, lactate production, and lactate modification within the synovial microenvironment are closely associated with glucose metabolism reprogramming. This reprogramming supports the elevated energy and nutrient requirement for abnormal immune cell activation and effector cell proliferation, thereby serving as a core event in RA pathogenesis. Traditional Chinese medicine (TCM) that modulates regulatory factors or pathological products related to glucose metabolism reprogramming in RA represents a promising therapeutic strategy for regulating immune responses and delaying disease progression. This review innovatively summarizes the distinct characteristics of glucose metabolism reprogramming in multiple immune and stromal cells (including fibroblast-like synoviocytes, macrophages, B cells, vascular endothelial cells and T cells) during RA progression, and systematically elucidates the regulatory mechanisms by which hypoxic microenvironments, lactate metabolism, and lactylation trigger glucose metabolic dysregulation. Furthermore, we provide a comprehensive and cutting-edge overview of the targeted modulatory effects of TCM monomers, active ingredients, and compound formulas on glucose metabolism reprogramming and lactylation in RA.
Abstract Renal fibrosis represents a shared pathological endpoint that drives the progression of chronic kidney disease (CKD) toward end-stage kidney disease (ESKD). Although current therapies can delay CKD progression, they have limited capacity to reverse established fibrotic remodeling, underscoring the need for mechanism-oriented anti-fibrotic interventions. Plant-derived preparations have long attracted attention because of their multi-component, multi-target, and multi-pathway pharmacological profiles. More recently, advances in separation, purification, and pharmacological evaluation have redirected research interest from crude extracts toward defined bioactive natural products. A growing body of evidence suggests that flavonoids, alkaloids, terpenoids, glycosides, polyphenols, quinones, and other natural products may exert anti-fibrotic effects by targeting key pathological processes, including inflammation, oxidative stress, mitochondrial dysfunction, metabolic reprogramming, autophagy dysregulation, epigenetic regulation, and regulated cell death. This review summarizes recent advances in the use of natural products for the treatment of renal fibrosis, with a particular focus on their underlying molecular mechanisms, current status of clinical translation, and the challenges that remain.
Yan Liu, Lei Gao, Hao Xu et al.· Renal Failure· 0 citations
: Pulmonary fibrosis is a chronic, progressive, and fatal interstitial lung disease characterized by excessive extracellular matrix deposition and irreversible parenchymal destruction, with idiopathic pulmonary fibrosis (IPF) as its most typical and lethal subtype. IPF confers an extremely poor prognosis, with a median survival of only 2–3 years after diagnosis and no curative therapies available to date. Mounting evidence has validated that the bidirectional crosstalk between glycolytic metabolic reprogramming and epigenetic modifications acts as a core mechanism sustaining the activated phenotype of pulmonary myofibroblasts and reinforcing the pathological progression of pulmonary fibrosis. This review summarizes the signature features of hyperactive glycolysis in pulmonary myofibroblasts, with a focus on the direct regulatory effects of glycolysis-derived metabolites on epigenetic programming: nuclear acetyl-CoA accumulation provides abundant substrates for histone acetylation; an imbalanced NAD⁺/NADH ratio suppresses the catalytic activity of Sirtuin family deacetylases; lactate overload induces novel histone lactylation modifications that modulate gene transcription; and α - ketoglutarate depletion and competitive inhibition dampen DNA/histone demethylase activity. Furthermore, we discuss the reverse reinforcing effect of epigenetic remodeling on the persistent expression of glycolysis-related genes, highlighting a reciprocal positive feedback loop between metabolic and epigenetic alterations. This crosstalk network offers a critical theoretical basis and actionable targets for disrupting the pathological homeostasis of fibrosis and developing novel anti-fibrotic interventions
Pengcheng Wang¹, Liming Fan², Wei Xiao¹· International Journal of Fro...· 0 citations
Diabetic kidney disease, the leading cause of end-stage kidney disease worldwide, involves complex interactions beyond classical hemodynamic and oxidative stress pathways. Recent advances emphasize metabolic reprogramming in renal cells—characterized by mitochondrial dysfunction, impaired fatty acid oxidation, lipotoxicity, and glycolytic shifts—as upstream drivers of cellular injury and fibrosis. Single-cell RNA sequencing reveals profound immunometabolic heterogeneity, including dynamic macrophage subpopulations (e.g., proinflammatory early states transitioning to TREM2hi/MRC1hi lipid-associated phenotypes) and T helper 17/regulatory T imbalance, which amplify inflammation via bidirectional crosstalk with podocytes, tubular cells, and mesangial cells. Interorgan axes, particularly gut dysbiosis and uremic toxin accumulation, further perpetuate immune dysregulation. This review integrates these insights to propose precision strategies targeting mitochondrial homeostasis, ferroptosis inhibition, glycolytic blockade in immune cells, and multimodal therapies (e.g., combination strategies integrating sodium–glucose cotransporter 2 inhibitors with immunometabolic modulators). Multi-omics integration and spatial transcriptomics hold promise for individualized and mechanism-guided interventions to halt diabetic kidney disease progression.
Zi-Yue Zhang, Yilun Qu, Xiaocheng Wang et al.· Research· 0 citations