Multi-omics integration and spatial transcriptomics hold promise for individualized and mechanism-guided interventions to halt diabetic kidney disease progression and propose precision strategies targeting mitochondrial homeostasis, ferroptosis inhibition, glycolytic blockade in immune cells, and multimodal therapies.
Abstract
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.
New evidence supports metabolic crosstalk between immune cells and fibroblasts as a key mechanism driving fibrotic remodeling and 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
A new perspective is provided for understanding why shared metabolic reprogramming in diabetes produces tissue-specific pathological outcomes, including filtration-barrier injury, vascular leakage, impaired wound healing, neuropathic injury, and cardiac dysfunction.
Q. Gong, Wei Zhao, Jing Xia et al.· Frontiers in Immunology· 0 citations
Diabetic cardiomyopathy (DCM) is a specific cardiac complication of diabetes that occurs independently of hypertension and coronary artery disease. Beyond metabolic disturbance, chronic hyperglycemia triggers immune dysfunction, contributing to myocardial inflammation, remodeling, and contractile impairment. This review highlights the critical roles of multiple immune cell populations-including monocytes, macrophages, mast cells, neutrophils, and T lymphocytes-in the pathogenesis of DCM, and frames DCM as an immunometabolic disorder driven in part by trained immunity. Hyperglycemia enhances glycolysis in macrophages and neutrophils, leading to the accumulation of acetyl-CoA that serves as a substrate for histone acetyltransferases. The resulting hyperacetylation of histone H3 locks immune cells into a pro-inflammatory state even after glucose levels normalize and amplifies inflammasome activation via the NLRP3 pathway, thereby coupling metabolic reprogramming to epigenetic reprogramming and sustaining chronic inflammation. In parallel, hyperglycemia-induced metabolic changes promote reactive oxygen species (ROS) production and upregulate S100A8/A9 expression. The S100A8/A9 heterodimer engages the receptor for advanced glycation end products (RAGE) on myeloid progenitors, driving the expansion of monocytes/macrophages and pro-inflammatory neutrophils and further fueling adverse cardiac remodeling. We also summarize emerging immunomodulatory therapies, including anti-cytokine strategies, inhibitors of inflammatory signaling pathways, mesenchymal stromal cell (MSC)-based interventions, other cellular treatments, and nanotechnology-enabled delivery platforms, which have shown promising anti-inflammatory and cardioprotective effects in preclinical models and early clinical studies. Targeting trained immunity and immunometabolic pathways may offer novel opportunities to halt or even reverse DCM progression.
Jingyi Lv, Xiaoyi Bao, Xiaolu Jiao et al.· International Immunopharmaco...· 0 citations
Adipose tissue macrophages (ATMs) have emerged as central regulators at the interface of immunity and metabolism. Accumulating evidence indicates that ATMs play multifaceted roles in the initiation and progression of obesity-associated metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease. This review synthesizes current knowledge on ATM functional diversity, with a particular focus on microenvironment-driven polarization, metabolic reprogramming, intercellular communication, and cross-organ immune regulation. We highlight how lipid overload, inflammatory mediators, and oxidative stress cooperatively shape ATM fate and function, endowing these cells with dual capacities to preserve tissue homeostasis or to propagate chronic metabolic inflammation. From a translational perspective, ATMs represent attractive biomarkers and therapeutic targets. Emerging strategies-including small-molecule modulators, natural compounds, and macrophage-targeted delivery systems such as miRNA-loaded nanoparticles-have demonstrated promise in reprogramming ATM phenotypes and alleviating metabolic dysfunction. Moreover, recent advances in single-cell omics, spatial transcriptomics, and fate-mapping technologies are redefining our understanding of ATM heterogeneity and temporal dynamics in human adipose tissue, thereby enabling precision immunometabolic interventions. A deeper elucidation of the immunometabolic mechanisms governing ATMs will provide both a conceptual framework and therapeutic foundation for the precision treatment of metabolic diseases.
Qining Huang, Jingwen Tang, Xiaozhen Shu et al.· Cytokine· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally, yet therapeutic options remain limited. Macrophage metabolic reprogramming is increasingly recognized as an important contributor to disease progression. Hepatic macrophages from resident Kupffer cells (KCs) to infiltrating monocyte-derived macrophages (MoMFs) and triggering receptor expressed on myeloid cells 2 (TREM2) + lipid-associated macrophages (LAMs) shift their bioenergetic profile from fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) toward aerobic glycolysis. This review maps the metabolic circuits driving macrophage-mediated inflammation in MASLD. We delineate how tricarboxylic acid (TCA) cycle disruption generates signaling metabolites that enforce glycolytic commitment through hypoxia-inducible factor stabilization, how metabolic-epigenetic coupling perpetuates inflammatory programs, and how the failure of repair mechanisms and mitochondrial quality control accelerates tissue damage. Notably, the IRG1-itaconate axis exhibits a dynamic U-shaped trajectory across MASLD stages: itaconate levels decrease during early steatosis due to Kupffer cell loss, but subsequently rise markedly during MASH as infiltrating macrophages upregulate IRG1 expression, representing a compensatory yet insufficient anti-inflammatory response. We further examine how these metabolic states evolve across disease stages, from simple steatosis through steatohepatitis and fibrosis to cirrhosis, and assess the therapeutic potential of metabolic interventions. Recent FDA accelerated approvals of resmetirom and semaglutide for selected adults with non-cirrhotic MASH and F2-F3 fibrosis have expanded the therapeutic landscape. Their clinical benefits are primarily supported by histological endpoints; whether modulation of hepatic macrophage metabolism contributes directly to these benefits remains to be established. Emerging evidence indicates that macrophage metabolic states retain plasticity and can be pharmacologically reprogrammed, with single-cell metabolomics poised to guide precision therapeutic strategies.
Li Zhu, Bo Wu· Frontiers in Immunology· 0 citations
Immunometabolism, an emerging field exploring metabolic reprogramming and functional regulation in immune cells, offers a lens for understanding complex diseases. This review delineates core concepts, key signalling nodes—emphasising the mechanistic target of rapamycin (mTOR) as an integrator of metabolic and immune signals—research and intervention strategies across metabolic and infectious diseases. Immune cells display metabolic plasticity: At rest, they depend mainly on mitochondrial oxidative phosphorylation, but swiftly shift to aerobic glycolysis upon activation to fuel effector functions. Pro‐inflammatory subsets like Th1 cells and M1 macrophages lean heavily on glycolysis, whereas regulatory T cells favour fatty acid oxidation. Central pathways—glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism—directly shape immune activation and inflammation via intermediates and regulatory enzymes. For example, succinate and itaconic acid are critical in inflammation control, while fatty acid and cholesterol metabolism dictate immune cell fate. In metabolic disorders such as obesity, diabetes, fatty liver disease, and atherosclerosis, immune metabolic reprogramming is the main driver of chronic low‐grade inflammation and tissue injury. During infection, a metabolic tug‐of‐war ensues: Pathogens hijack host metabolism for survival, and the host counters by reprogramming its own metabolism. The idea of “trained immunity” highlights how metabolism–epigenetics crosstalk endows innate immunity with memory‐like capacity. These insights inform therapeutic avenues—modulating metabolic pathways, nutritional interventions, and microbiome targeting—with wide potential. Challenges remain, including the complexity of in vivo networks and the need for precise interventions. Yet advances in single‐cell multi‐omics and metabolic flux analysis will deepen mechanistic understanding and enable breakthroughs in precision strategies.
Wen-Bin Tan· Scandinavian Journal of Immu...· 0 citations
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