Immuno-metabolic reprogramming in pulmonary fibrosis: Emerging therapeutic targets beyond inflammation.

Recent understanding of immunometabolic remodeling in pulmonary macrophages: homeostasis, chronic respiratory diseases, and therapeutic targeting

Pulmonary macrophages are essential regulators of immune surveillance, tissue homeostasis, and inflammatory responses within the respiratory microenvironment. Emerging evidence indicates that chronic environmental stress and persistent injury induce profound immunometabolic remodeling in these cells, thereby contributing to the development and progression of chronic lung diseases. Under physiological conditions, pulmonary macrophages maintain metabolic homeostasis primarily through oxidative phosphorylation and fatty acid oxidation. However, pathological conditions drive metabolic reprogramming characterized by altered glycolysis, mitochondrial dysfunction, oxidative stress, lipid dysregulation, and disturbed iron homeostasis, leading to persistent inflammation, impaired tissue repair, and progressive remodeling. Recent studies have further highlighted the critical interplay between metabolic pathways, redox signaling, and immune regulation in shaping macrophage phenotypes and functions. Importantly, therapeutic strategies targeting macrophage metabolism and redox balance, together with advances in macrophage-directed drug delivery systems, have emerged as promising approaches for modulating pulmonary inflammation and tissue injury. This review summarizes recent understanding of immunometabolic remodeling in pulmonary macrophages under homeostatic and pathological conditions and discusses emerging therapeutic perspectives targeting macrophage metabolism in chronic respiratory diseases.

Organelle Crosstalk and Metabolic Reprogramming in Idiopathic Pulmonary Fibrosis: Mechanisms and Therapeutic Implications

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease of unknown cause, marked by excessive deposition of extracellular matrix (ECM) components such as collagen. This pathological accumulation results in progressive destruction of the lung architecture and ultimately leads to respiratory failure. Growing evidence indicates that dysfunction across multiple cell types is an important driver of IPF. Nevertheless, its underlying pathobiology remains incompletely understood. The normal integrity of organelles is critical for cellular function, and in different IPF lung cells, such as alveolar epithelial cells (AECs), fibroblasts, and macrophages, we found dysfunctional development of key organelles and metabolic reprogramming changes driving malignant progression of pulmonary fibrosis. This review summarizes the contributions of key organelles—mitochondria, the endoplasmic reticulum, lysosomes, and peroxisomes—and functional changes in metabolic reprogramming during IPF progression. We further clarify the core mechanisms of how inter‐organelle network disruptions drive fibrosis, with the goal of identifying critical organelle nodes to disrupt pathogenic metabolic reprogramming and ultimately provide a rationale for developing new treatments.

Autophagy-Targeted Vascular Remodeling in Pulmonary Arterial Hypertension: Molecular Mechanisms and Therapeutic Perspectives

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by progressively increased pulmonary vascular resistance and right heart failure. Its pathogenesis involves multiple factors, including genetic predisposition, inflammation, oxidative stress, and imbalances between cell proliferation and apoptosis. Recent studies indicate that autophagy has a context-dependent dual role in PAH. Flux-competent autophagy may be protective by clearing damaged mitochondria, limiting excessive inflammation, and maintaining metabolic homeostasis, whereas excessive autophagy initiation or impaired autophagosome-lysosome degradation may promote metabolic dysfunction, inflammatory signaling, abnormal vascular cell phenotypes, and pulmonary vascular remodeling. This focused narrative review summarizes the molecular mechanisms and key signaling pathways linking autophagy to PAH, with emphasis on PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) energy-sensing axis. It also evaluates potential therapeutic strategies targeting key nodes of autophagy, such as AMPK activators and mTOR inhibitors, along with their clinical research progress. Finally, this review provides an outlook on future research directions, emphasizing the need to further elucidate the dynamic regulatory mechanisms and cell-type specificity of autophagy in order to advance the clinical translation of autophagy-targeted precision therapies for PAH.

Metabolic Regulation of Macrophages in Health and Disease

Macrophages orchestrate immune responses through remarkable phenotypic plasticity, which is intrinsically linked to their ability to reprogram intracellular metabolic pathways in response to microenvironmental cues. While recent advances have highlighted the role of aberrant macrophage metabolism in diverse diseases, a systematic synthesis integrating both intracellular and extracellular metabolic signals remains lacking. This review provides a comprehensive framework for understanding how core metabolic pathways—glycolysis, the TCA cycle, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and amino acid metabolism—are rewired during macrophage polarization under the orchestration of upstream signaling cascades, including NF‐κB, PI3K/AKT/mTOR, JAK–STAT, and MAPK. We examine how exogenous metabolites such as succinate, itaconate, lactate, and amino acids reciprocally regulate macrophage function and discuss tissue‐specific metabolic signatures of macrophage subsets—including alveolar macrophages （AMs), Kupffer cells (KCs), and tumor‐associated macrophages (TAMs)—in the context of obesity, Type 2 diabetes (T2D), metabolic dysfunction‐associated steatotic liver disease (MASLD), infections, autoimmune disorders, and cancer. We further evaluate emerging therapeutic strategies targeting macrophage metabolism, summarizing preclinical and clinical advances across signaling pathways, metabolic nodes, cytokines, and cell‐based therapies with detailed trial data. By integrating cell‐intrinsic metabolic circuitry with extracellular signals, this review establishes a theoretical foundation for metabolism‐targeted immunotherapies and identifies key knowledge gaps for future investigation.

Molecular Mechanisms and Therapeutic Targeting of the Macrophage Metabolic-Epigenetic Interaction Network in Chronic Obstructive Pulmonary Disease

Metabolic reprogramming rewires aberrant immune responses to drive endothelial dysfunction in Kawasaki disease: a narrative review

Background and Objective Kawasaki disease (KD) is a systemic pediatric vasculitis characterized by dysregulated immune activation and substantial risk of coronary artery lesions. Emerging evidence suggests metabolic reprogramming is a critical link between immune responses and endothelial dysfunction during KD progression. This review aims to provide an integrated overview of metabolic alterations in KD pathogenesis, focusing on clinical observations, mechanistic insights, and experimental evidence. Methods A literature search was conducted using PubMed and Web of Science to identify studies published up to July 2026, combining “Kawasaki disease” with terms related to metabolism and metabolic pathways, including metabolites, glucose, glycolysis, amino acids, lipids, fatty acid oxidation, succinic acid, the tricarboxylic acid (TCA) cycle, nitric oxide, urine, gut microbiota, mouse models, and therapeutic strategies. Relevant clinical, experimental, and mechanistic studies were reviewed and synthesized. Key Content and Findings Accumulating evidence indicates extensive metabolic remodeling in KD, including enhanced glycolysis, disrupted lipid metabolism and fatty acid oxidation, altered amino acid metabolism, and TCA cycle perturbations. These abnormalities are closely linked to immune activation, mitochondrial dysfunction, oxidative stress, and vascular inflammation. KD mouse models further support metabolic reprogramming, marked by altered tryptophan and amino acid metabolism, lipid metabolism, and lactate production. Notably, kynurenine pathway activation with reduced tryptophan availability is associated with inflammatory amplification and mitochondrial impairment. Beyond host-derived changes, gut microbiota dysbiosis and its metabolites appear to correlate with immune responses and disease severity. However, clinical translation of these metabolic signatures into reliable biomarkers or therapeutic targets remains limited. Conclusions This review highlights metabolic reprogramming as a key interface linking immune dysregulation, endothelial injury, and vascular complications in KD. Metabolic abnormalities may act not merely as consequences of inflammation but as active regulators of vascular dysfunction and disease progression. Significant gaps remain in establishing causal relationships between specific metabolic alterations and KD pathogenesis. Future studies integrating multicenter cohorts with cellular, multi-omics, and animal model approaches, particularly centered on the metabolic-immune-vascular injury axis, will be essential for identifying novel biomarkers and therapeutic strategies.