Endoplasmic Reticulum Stress-Driven Inflammatory Mediators in Metabolic Disorders: From Molecular Mechanisms to Targeted Therapies.

NLRP3 inflammasome in cardiovascular diseases: molecular mechanisms and advances in targeted drug research

The NLRP3 inflammasome plays a pivotal role in innate immune responses and has emerged as an important contributor to the pathogenesis of cardiovascular diseases (CVDs), including atherosclerosis, heart failure, myocardial infarction, and hypertension-related organ damage. Upon activation, NLRP3 promotes the maturation and release of IL-1β and IL-18 and triggers pyroptosis, thereby exacerbating endothelial dysfunction, vascular smooth muscle cell proliferation and migration, lipid metabolic disorders, and adverse myocardial remodeling. These processes form a self-perpetuating cycle of inflammation and tissue injury. Therapeutic strategies targeting the NLRP3 pathway have progressed from non-specific anti-inflammatory agents, such as aspirin and colchicine, to more precise interventions that block NLRP3 oligomerization (e.g., MCC950 and its analogs), neutralize upstream cytokines, modulate metabolic and oxidative stress pathways, and employ advanced delivery systems including gene editing and nanocarriers. Despite these advances, current approaches are limited by insufficient target specificity, incomplete long-term safety data, and the absence of disease subtype-specific regimens. This review provides a comprehensive overview of multi-level therapeutic strategies directed against the NLRP3 inflammasome, critically evaluates preclinical and clinical evidence—including findings from the CANTOS trial—and discusses the translational potential of NLRP3-targeted immunometabolic therapy in CVDs. Looking forward, integration of multi-omics technologies, such as single-cell sequencing and spatial transcriptomics, with well-designed clinical studies will be essential to delineate the context-specific roles of NLRP3 across different CVD subtypes and to clarify its interactions with protective pathways such as AMPK and SIRT1. These efforts may facilitate the development of more selective, tissue-targeted, and safer therapeutic agents for the precision management of cardiovascular diseases.

Molecular Insights into Signalling Pathways and Therapeutic Monitoring of Chronic Low-grade Inflammation-associated Obesity

Obesity has emerged as a major global public health concern. It is a multifactorial condition encompassing genetic, environmental, socioeconomic, and psychosocial factors. This narrative review aims to highlight the key pathophysiological processes associated with chronic low-grade inflammation (CLGI) in obesity. Data collection was performed using the PubMed, Scopus, Web of Science, and Google Scholar databases, using the search terms “chronic low-grade inflammation”, “pathophysiology of obesity,” and “metabolic syndrome” to obtain relevant articles. The pathophysiological sequence underlying CLGI-associated obesity begins with adipose tissue expansion, during which hypertrophic adipocytes trigger cellular stress manifested as hypoxia and ER stress, accompanied by the release of damage-associated molecular patterns (DAMPs). This initiates a vicious cycle involving the recruitment of macrophages and their proinflammatory M1 polarization, with activation of inflammatory pathways, such as NF-κB and the NLRP3 inflammasome. These changes further contribute to the induction of systemic insulin resistance and metabolic dysregulation. Both tissue and systemic biomarkers are valuable in identifying and monitoring CLGI-associated obesity. Treatment approaches ranging from pharmacological agents and bariatric surgery to dietary modifications, exercise, and microbiome-based therapies are relevant for managing inflammation and metabolic health. In conclusion, strategic immunotargeting of CLGI through context-specific interventions can serve as an innovative therapeutic strategy to treat CLGI-associated obesity and potentially mitigate the resulting comorbid metabolic burden. Future efforts should prioritize the development of multi-marker approaches within precision medicine frameworks to enable more individualized care for patients with CLGI-associated obesity.

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.

Adipose tissue macrophages in metabolic inflammation and disease: Insights from single-cell and multi-omics studies.

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.

Microbiota–innate immune crosstalk drives atherosclerosis: mechanisms, disease progression, and emerging therapeutic strategies

Atherosclerosis (AS) is a complex cardiovascular disease driven by the interplay of dysregulated lipid metabolism, chronic inflammation, and immune dysfunction. Increasing evidence has revealed that the gut microbiota not only regulates host metabolic homeostasis but also actively contributes to the initiation and progression of AS through intricate interactions with the innate immune system. Microbial-derived signaling molecules, including lipopolysaccharides, outer membrane vesicles, extracellular nucleic acids, and TMAO, can activate Toll-like receptors, the NLRP3 inflammasome, and nucleic acid–sensing pathways, thereby promoting inflammatory cytokine production, endothelial dysfunction, and foam cell formation. In contrast, beneficial microbial metabolites such as short-chain fatty acids, bile acids, and tryptophan-derived metabolites exert immunomodulatory and vasculoprotective effects through signaling pathways involving FFAR2/3, the AhR, the FXR, and TGR5. Conversely, the innate immune system shapes microbial composition and function through barrier defense, phagocytic clearance, and antimicrobial factor production, establishing a dynamic and reciprocal microbiota–immune interaction network. This review systematically summarizes alterations in microbial ecology and innate immune homeostasis associated with atherosclerosis, elucidates the key molecular mechanisms underlying microbiota–innate immune crosstalk, and examines its dynamic involvement across four critical stages of disease evolution: endothelial dysfunction, foam cell formation, plaque progression, and plaque destabilization and rupture. In addition, emerging therapeutic approaches, including microbiota remodeling, modulation of microbial metabolic pathways, and precision microbiome-based interventions, are comprehensively discussed. The microbiota–innate immune axis provides a novel conceptual framework for understanding atherosclerosis pathogenesis and represents a promising target for future disease prevention, risk stratification, and precision therapeutics.

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