Immune

Mitochondria have long been viewed as the "powerhouses" of the cell, but research over the past decade has established that they play a far more complex role in skin immune homeostasis beyond ATP production. The metabolic preferences of immune cells and skin parenchymal cells-glycolysis, oxidative phosphorylation, or fatty acid oxidation-determine their fate choices during inflammatory responses. When mitochondrial function is impaired, the release of damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and mitochondrial ROS can activate the cGAS-STING and NOD-like receptor family pyrin domain-containing 3 inflammasome pathways, driving inflammatory cycles in various skin diseases including psoriasis, atopic dermatitis, lupus erythematosus, and vitiligo. This review systematically examines the key mechanisms of mitochondrial metabolic reprogramming in skin immune disorders, focusing on 3 typical scenarios: the metabolic preferences of immune cells, mitochondrial DAMP-mediated autoinflammation, and the impact of mitochondrial dynamics imbalance on tissue-resident memory T cell function. Furthermore, we evaluate clinical evidence for repurposing old drugs such as metformin and thiazolidinediones, and discuss the translational prospects of emerging strategies including Nrf2 agonists, mitophagy inducers, and targeted nanocarriers. Understanding the "dual identity" of mitochondria in skin immunity-as both metabolic regulators and signaling sensors-will lay the foundation for developing precise metabolic immunomodulatory therapies.

Neutrophil extracellular trap-driven necrosis-related genes (NRGs) and inflammation-related genes (IRGs) are crucial in mitigating or inhibiting cancer progression in breast cancer patients. The interaction between NRGs and IRGs in breast cancer remains unclear. Thus, identifying prognostic genes associated with NETosis and inflammation in breast cancer may offer a novel approach to improving the outcome of breast cancer. Genes with statistically significant expression levels and correlations with IRGs and NRGs scores were selected as candidate genes, and the protein-protein interactions of the encoded proteins were explored. Subsequently, prognostic genes were further identified and build the risk model. Lastly, independent prognostic factors were determined through independent prognostic analysis, a prognostic model was established, and the immune microenvironment and drug sensitivity were analyzed. The study identified ZMYND10, IL12B, CXCL13, TFF1, LTB, and SPIB as prognostic genes. Additionally, risk score and three clinical features, including age, were established as independent prognostic factors. A prognostic model with moderate predictive accuracy was developed. Further analysis revealed that six prognostic genes were considerably correlated with differential immune cells, among which CXCL13, IL12B, LTB, and SPIB were considerably positively correlated with most differential immune cells. Additionally, 18 drugs were considerably associated with the risk score, including six drugs such as Metformin and Thapsigargin, which could potentially be used to treat breast cancer. This study constructed a risk model and a nomogram for breast cancer prognosis using bioinformatics methods, and analyzed prognostic genes of breast cancer, which will be helpful to the improvement of breast cancer's outcome and the development of clinical medicine.

Despite increasing evidence supporting the promising anti-diabetic potential of natural polysaccharides, studies on structurally well-defined polysaccharides and their systemic mechanisms of action in type 2 diabetes mellitus (T2DM) remain limited. Here, we characterize GFP-Z, a bioactive α-glucan (1760.0 kDa) isolated from Grifola frondosa, which features an α-1,4-linked backbone with α-1,6, α-1,3 and α-1,2 branches. Pharmacological evaluation in db/db mice showed that GFP-Z administration significantly alleviated hyperglycemia and diabetic symptoms, with glucose-lowering effects comparable to metformin under the tested conditions, without causing apparent hepatorenal toxicity. Integrated multi-omics analyses, biochemical assays, and a preliminary pharmacological attenuation experiment further suggest that GFP-Z may exert its effects, at least in part, through immunomodulation-associated metabolic regulation, as reflected by reduced hepatic M1-type macrophage infiltration, altered circulating cytokines and hepatic immunometabolites, activation of the hepatic JAK/STAT-PI3K/AKT signaling axis, and attenuation of GFP-Z-associated immune and glucose-lowering responses by tofacitinib. Taken together, our findings suggest that GFP-Z may represent a promising bioactive polysaccharide capable of improving metabolic disorders in T2DM, potentially through systemic immunomodulation-associated metabolic regulation.

Diabetes mellitus, especially type 2 diabetes (T2DM), is a complex metabolic disease marked by persistent low-grade inflammation and insulin resistance. In diabetes, adipose tissue macrophages adopt a pro-inflammatory M1 phenotype, secreting cytokines including TNF-α, IL-6, and IL-1β that disrupt insulin signaling and cause metabolic dysfunction. AMP-activated protein kinase (AMPK), a cellular energy sensor, is a key regulator of macrophage polarization. It suppresses M1 responses by inhibiting NF-κB and JNK signaling, activating CREB/SIRT1 pathways, and promoting oxidative metabolism. Therefore, this review investigates the bidirectional interaction between AMPK signaling and macrophage function in diabetes, focusing on how metabolic stress affects AMPK activity, increasing inflammation and insulin resistance, whereas AMPK activation restores immune-metabolic balance. The gut microbiome further influences this axis, with short-chain fatty acids activating AMPK via GPR41/43, promoting M2 polarization and improving metabolic outcomes. Metformin, SGLT2 inhibitors, new direct AMPK activators such as PXL770, and lifestyle changes are also potential therapeutic treatments. However, considerable hurdles remain, including the prevalence of preclinical findings, a lack of macrophage-specific AMPK activators, simplicity of the M1/M2 paradigm, and uncertainty about long-term safety. Future research must focus on macrophage-targeted drug delivery, tissue-specific regulatory networks, biomarker discovery, and rigorous clinical trials with immunological outcomes. In conclusion, the AMPK-macrophage axis is a critical immune-metabolic gatekeeper in diabetes, and targeting this pathway offers a potential technique for restoring immune-metabolic balance, while significant difficulties must be overcome before practical use.

Gestational diabetes mellitus (GDM) is a major public health challenge characterized by placental immunometabolic dysregulation. This study aimed to identify molecular signatures associated with GDM-related placental pathology and evaluate their diagnostic and therapeutic implications. Two bulk placental transcriptomic datasets (GSE70493 and GSE263483) and one single-cell dataset (GSE173193) were analyzed. Differential expression analysis, WGCNA, and machine-learning feature selection (LASSO and SVM-RFE) were used to identify candidate gene signatures. A two-gene logistic regression model was constructed and externally validated. Immune-cell correlation rewiring and single-cell in silicoperturbation analysis explored immune-network alterations and regulatory roles of identified genes. A drug-prioritization framework was used for therapeutic screening. Intersecting WGCNA modules with differentially expressed genes identified 29 candidates enriched in antigen presentation and mononuclear phagocyte functions. Dual-algorithm selection converged on HLA-DQA2 and FGL2. The two-gene model achieved an AUC of 0.786 in the discovery cohort and 0.813 in the external validation cohort. Immune rewiring analysis indicated a shift toward M1 macrophage polarization. Single-cell perturbation analysis supported regulatory roles of HLA-DQA2 and FGL2 within the macrophage lineage. Drug analysis reaffirmed insulin, metformin, and glyburide as stable therapeutic anchors. The HLA-DQA2/FGL2 signature captures key aspects of placental immunometabolic dysregulation in GDM, including altered antigen presentation and macrophage-associated immune rewiring. This integrated framework provides candidate biomarkers for GDM risk stratification and generates computational hypotheses for future mechanistic and therapeutic studies.

The paracrine crosstalk between macrophages and granulosa cells, forming a "macrophage M1 polarization-inflammation-pyroptosis" vicious cycle in the ovarian immune microenvironment, promotes premature ovarian insufficiency (POI) progression. This study aimed to investigate the therapeutic potential of metformin-capped silver nanoparticles (Met-AgNPs) in disrupting pathological paracrine signaling axis and restoring ovarian function. Met-AgNPs and control AgNPs were synthesized and physicochemically characterized. Dynamic light scattering (DLS) was conducted to evaluate the hydrodynamic diameter, polydispersity index (PDI), and zeta potential of the nanoparticles in different dispersion media (deionized H2O, PBS, DMEM). The in vitro release kinetics and in vivo biodistribution were also evaluated. THP-1-derived macrophages were induced to M1 polarization and treated with Met-AgNPs, AgNPs, or metformin, followed by assessment of macrophage polarization states. The conditioned medium (CM) from these macrophages was then applied to human granulosa KGN cells to evaluate its effects on NLRP3 inflammasome activation and pyroptosis. A cyclophosphamide (CTX)-induced POI rat model was established and treated with Met-AgNPs, AgNPs, or metformin. Ovarian function was evaluated via estrous cycle, hormone levels, follicle counting, and fertility assessment. Ovarian histopathology, macrophage polarization, inflammation, and NLRP3-driven pyroptosis were assessed. Met-AgNPs exhibited a spherical morphology, smaller hydrodynamic diameter, and enhanced colloidal stability compared to AgNPs. Crucially, Met-AgNPs demonstrated sustained drug release and achieved targeted accumulation with localized retention in inflamed ovaries. In vitro, treatment with Met-AgNPs, AgNPs, or metformin all reprogrammed M1 macrophages towards M2 phenotype, accompanied by decreased pro-inflammatory cytokine secretion and increased anti-inflammatory cytokine secretion. The CM from all treated macrophages inhibited NLRP3 inflammasome activation and pyroptosis in KGN cells. Notably, Met-AgNPs demonstrated superior efficacy among all treatment groups. In POI rats, Met-AgNPs treatment restored estrous cycles, serum hormone levels, and healthy follicle count, and improved fertility. These improvements were mechanistically associated with the inhibition of M1 macrophage infiltration and NLRP3-driven pyroptosis within the ovarian tissues. Met-AgNPs ameliorated POI by reprogramming macrophage polarization from M1 to M2 phenotype and then inhibiting NLRP3-dependent pyroptosis in granulosa cells. Our findings propose Met-AgNPs as a promising nanotherapeutic strategy for alleviating ovarian inflammation and restoring fertility in POI.

Type 2 diabetes mellitus (T2DM) increases vulnerability to cognitive decline through interacting disturbances in insulin signaling, mitochondrial energetics, redox and lipid homeostasis, neuroimmune regulation, neurovascular coupling, and experience-dependent plasticity. This review integrates molecular, cellular, preclinical, and clinical evidence linking these processes to altered gene expression, glial dysfunction, synaptic instability, and impaired cognition. We distinguish well-supported mechanisms from unresolved questions concerning causality, cell-type specificity, human hippocampal remodeling, context-dependent pharmacological effects, and the translational limitations of experimental models. On this basis, we propose an integrative framework in which metabolic flexibility acts as a permissive gatekeeper for neural adaptation. AMPK-centered signaling supports mitochondrial quality control, autophagy, antioxidant defenses, and restraint of NF-kB/NLRP3-associated inflammation, but is considered necessary rather than sufficient for cognitive recovery. Durable plasticity additionally requires activity-dependent CREB-BDNF signaling and adequate neurovascular support to match energy delivery with circuit demand. Exercise, cognitive training, environmental enrichment, metformin, and incretin-based therapies engage complementary components of this network, although their efficacy is likely to vary with age, metabolic state, inflammatory burden, vascular reserve, treatment timing, and adherence. The framework predicts that metabolic activation without circuit engagement will provide limited cognitive benefit, whereas plasticity-promoting interventions will be constrained by persistent metabolic or vascular dysfunction. We therefore argue for multimodal, biomarker-informed strategies that integrate metabolic stabilization, vascular support, and structured physical and cognitive stimulation. Long-term randomized studies combining neuroimaging with molecular and metabolic profiling are required to test these predictions and define precision approaches for preserving cognitive resilience in T2DM.

Development of Immunometabolism as a central paradigm in the modern immunology has revolutionized the understanding of metabolism from being a passive supplier of energy to an important determinant of immune cell fate and function. Immune cells are activated, differentiated, survive and undergo programmed cell death through the activity of distinct metabolic programs, including those involving glycolysis, oxidative phosphorylation (OXPHOS), nutrient sensing through Mechanistic Target of Rapamycin (mTOR), AMP-Activated Protein Kinase (AMPK), and HIF‑1α. Rapid proliferation and production of cytokines by effector T cells and pro-inflammatory macrophages is mediated by glycolysis, while persistence and tolerance by memory T cells and reparative macrophages is mediated by oxidative metabolism. Metabolic input and output are also coupled with immune specialization and cell death mechanisms, such as apoptosis, Pyroptosis and ferroptosis, via mitochondrial bioenergetics and production of Reactive Oxygen Species (ROS). Altered immunometabolism is linked to a variety of pathologies: competition for nutrients in tumor physiology leads to T cell exhaustion; an unchecked glycolytic pathway maintains a state of autoimmune inflammation; pathogens exploit host metabolism to escape immunological control; and metabolic diseases, such as obesity and diabetes, foster chronic low‑grade inflammation. Therapies such as rapamycin, metformin, glycolysis and glutamine inhibitors, and metabolic adjuvants in vaccines underscore the translational potential of targeting metabolic checkpoints. But there are still debates on the specificity of the metabolic intervention, the balance between the effector and regulation responses, and the restrictions of the existing experimental models. New strategies, such as single-cell metabolomics and precision medicine, are expected to bring in more sophisticated ways for fine-tuning immune metabolism. Immunometabolism is thus a paradigm shift, with metabolism now being at the heart of immune regulation, and providing new opportunities for critical evaluation and translational innovation in cancer, autoimmunity, infections and metabolic disease.

Latent autoimmune diabetes in adults (LADA) and Graves disease (GD) may coexist due to shared autoimmune mechanisms and genetic susceptibility. We report a 39-year-old woman with class III obesity who presented with palpitations, blurry vision, and hypertension. Evaluation revealed new-onset diabetes (hemoglobin A1c 8.3% [SI: 67 mmol/mol]; reference range, 4.6-6.4% [SI: 27-46 mmol/mol]) and hyperthyroidism with suppressed thyroid stimulating hormone and elevated free thyroxine (free T4), along with positive thyroid peroxidase and thyrotropin receptor antibodies, confirming GD. Further testing demonstrated markedly elevated glutamic acid decarboxylase-65, zinc transporter 8, and insulinoma-associated antigen-2 antibodies. C-peptide was 2.34 ng/mL (SI: 0.78 nmol/L) (reference range, 0.80-3.85 ng/mL [SI: 0.26-1.27 nmol/L]) with a glucose of 92 mg/dL (SI: 5.1 mmol/L) (reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]), consistent with early LADA. She was treated with methimazole and metformin as she was quite averse to insulin therapy and was able to achieve good glycemic control. At 23 months, worsening hyperglycemia with declining C-peptide level, necessitated multiple daily insulin injections and continuous glucose monitoring. This case highlights the biphasic course of LADA and the importance of screening for additional autoimmune diseases, consistent with autoimmune polyglandular syndrome type 3.

Alzheimer's disease (AD) is increasingly recognized as a disorder driven by dysregulated innate immunity rather than merely amyloid‑β accumulation. Microglia, the brain's resident innate immune cells, acquire long‑term functional memory, a process known as trained immunity or innate immune memory, through epigenetic and metabolic reprogramming. In AD, chronic exposure to amyloid‑β and tau aggregates locks microglia into a maladaptive primed state characterized by altered histone modifications (H3K4me3, H3K27ac), sustained glycolysis via the HIF‑1α/mTOR axis, and impaired phagocytic function, perpetuating neuroinflammation and neurodegeneration. This review critically synthesizes recent advances that define the molecular architecture of microglial immune memory, including epigenetic rewiring, immunometabolic shifts, and intercellular crosstalk with astrocytes and the gut microbiome. We evaluate the emerging immunopharmacological toolbox designed to reverse maladaptive priming and restore neuroprotective resilience, focusing on small‑molecule NLRP3 inflammasome inhibitors (HT‑6184, DFV890, BGE‑102), TREM2 agonists (VG‑3927, MNA‑001), metabolic modulators (metformin, rapamycin), trained immunity‑based vaccination (BCG), specialized pro‑resolving mediators (maresin 1, resolvin D1, lipoxin A4), and senolytics. Clinical‑stage agents and their mechanisms of action are highlighted. We argue that the next generation of AD therapeutics must move beyond target suppression toward the functional reprogramming of brain innate immunity, and we propose a biomarker-guided, patient-stratified framework that integrates multimodal immunopharmacology, combining NLRP3 inhibition, TREM2 agonism, metabolic reprogramming, and resolution pharmacology to restore immune homeostasis. Harnessing the plasticity of innate immune memory offers a transformative paradigm for disease‑modifying therapy in AD.

The convergence of metformin and cancer immunotherapy has recently gained intense global interest, driven by evidence that metformin can remodel the tumor immune microenvironment and potentiate immune-based treatments. No bibliometric study has yet mapped this rapidly expanding field. We searched the Web of Science Core Collection from January 1, 2007, to July 8, 2026, for English papers containing metformin and immunotherapy terms, retrieving 328 papers. VOSviewer 1.6.19 and CiteSpace 6.2.R4 were used to quantify publications, citations, collaboration networks (countries, institutions, and authors), keyword co-occurrence, citation bursts, and temporal trends. The compound annual growth rate (CAGR) was 26.71% per year; 93.3% of papers were published after 2018. In the mapped country network, China contributed the most publications (n = 167), whereas the United States had the highest citation count (4402) and total link strength (56). Sun Yat-sen University led institutional output (n = 12), and Heiichiro Udono was the most productive mapped author (n = 8). The Journal for ImmunoTherapy of Cancer was the leading publication source (n = 12). Research on metformin plus immunotherapy is surging. Future priorities include elucidating the impact of metformin on immunotherapeutic efficacy across tumor types, optimizing combination regimens, and identifying predictive biomarkers-areas in which high-quality international collaboration will be critical.

As the most prevalent subtype of colorectal cancer, microsatellite-stable colorectal cancer (MSS CRC) is resistant to T cell-focused immune checkpoint blockade due to its low mutational burden and immunosuppressive tumor microenvironment. Despite reprogramming tumor-associated macrophages toward a tumoricidal M1-like state being a promising alternative, its efficacy is limited by paradoxical upregulation of programmed cell death-ligand 1 (PD-L1) on M1-like macrophages and their inherently poor antigen cross-presentation capacity. Here, we report that poly-metformin (PMet) can mimic the intracellular domain of PD-L1, competitively inhibit the membrane anchoring of PD-L1, and thereby effectively downregulate cell-surface PD-L1. To evaluate the therapeutic efficacy of PMet in immunosuppressive MSS CRC, we further developed an oral probiotic outer membrane vesicle (OMV) gene delivery system, siYthdf2/PMet@Akk-OMV, and demonstrated its ability to reduce PD-L1 levels on both macrophages and tumor cells while synergistically enhancing macrophage cross-presentation of tumor antigens, leading to potent activation of specific antitumor immunity and significant tumor growth inhibition. This work thus provides both theoretical and experimental foundations for treating cancers resistant to traditional immune checkpoint blockade therapy.

Pernicious anemia (PA) is an autoimmune cause of vitamin B12 deficiency, often secondary to chronic atrophic gastritis, which increases the risk of gastric malignancies. Early signs, like mild macrocytosis, are frequently overlooked, especially in patients with other risk factors such as long-term metformin use. We present a case illustrating the full clinical trajectory from long-standing, unexplored macrocytosis to severe anemia, ultimately leading to the diagnosis of PA and detection of early-stage gastric adenocarcinoma on surveillance esophagogastroduodenoscopy (EGD). Informed consent was obtained from the patient to publish the case. The patient was a 59-year-old man with type 2 diabetes, treated with metformin 2 g daily for over four years, who presented with severe symptomatic macrocytic anemia after approximately one year of unexplored macrocytosis on routine laboratory testing. Evaluation revealed profound vitamin B12 deficiency with evidence of hemolysis, and serologic testing confirmed PA. Surveillance EGD identified a gastric polyp, which was resected for histopathologic evaluation. Examination of the lesion revealed a moderately differentiated adenocarcinoma with associated high-grade dysplasia and submucosal invasion. Random gastric biopsies demonstrated chronic inflammation with focal atypia and were negative for Helicobacter pylori. Subsequent staging investigations confirmed stage I disease (cT1b, cN0, and cM0). The patient underwent partial gastrectomy and continued intramuscular vitamin B12 therapy, with excellent clinical recovery and no evidence of recurrent disease on follow-up. Our case highlights that persistent macrocytosis should not be overlooked, particularly in patients with risk factors for vitamin B12 deficiency such as long-term metformin use. Early evaluation may uncover important underlying diagnoses such as PA, prevent severe hematologic complications, and facilitate detection of associated gastric malignancies at a potentially curable stage.

Guidelines recommend Latent Autoimmune Diabetes in Adults be managed similar to type 1 diabetes, emphasizing early insulin initiation, while other guidances suggest incorporating non-insulin antihyperglycemic therapies based on comorbidities and C-peptide levels. The study objective was to explore whether glutamic acid decarboxylase-65 autoantibody detection in individuals diagnosed with type 2 diabetes impacts antihyperglycemic treatment. This retrospective, observational cohort study at an academic integrated delivery network in Northeast Ohio utilized electronic medical records. Included individuals were previously diagnosed with type 2 diabetes and tested positive for glutamic acid decarboxylase-65 autoantibodies between 9/1/2021 and 9/1/2023. The primary outcome compared the median number of non-insulin antihyperglycemic classes at the time of autoantibody detection and after 12 months. Participants had a mean age of 57.2 ± 13.7 years, 73.3% white, with a median body mass index of 26.2 kg/m2, and 82.1% had an estimated glomerular filtration rate greater than 60 mL/min/1.73 m2. A median of 1 (0-2) non-insulin antihyperglycemic classes were present at detection and 1 (0-1.5) post-detection (P < 0.0001). Significantly fewer individuals were prescribed metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, sulfonylureas, and thiazolidinediones, whereas significantly more individuals were prescribed bolus insulin post-detection. While most individuals had a baseline C-peptide within 12 months prior to detection, significantly fewer C-peptide assessments occurred during the subsequent 12-month follow-up period. In individuals with type 2 diabetes, glutamic acid decarboxylase-65 autoantibody detection was associated with significantly fewer non-insulin antihyperglycemics prescribed and significantly more insulins at 12 months post-detection.

Given the unprecedented rise in glucagon-like peptide-1 receptor analogue (GLP-1RA) therapy over the past decade, we aimed to investigate potential unintended laryngeal manifestations. A retrospective cohort study was conducted using the TriNetX United States Collaborative Network. Adults with obesity on GLP-1RA medications (n = 617,296) from January 1, 2016 to December 3, 2025, were compared with controls (n = 3,503,102), excluding patients with head and neck neoplasms, head and neck radiation therapy, autoimmune diseases, airway disorders or acute respiratory conditions via ICD-10 and CPT codes. Laryngeal symptoms within 1, 3, and 6 months of initiation of GLP-1RA were assessed in propensity score-matched cohorts by age, sex, race, and ethnicity. Outcomes were reported as risk differences (RD) and odds ratios (OR) with 95% confidence intervals (CI). GLP-1RA therapy increased the 6-month risk of any laryngeal manifestations (OR 1.19, 95% CI 1.16-1.21; p < 0.0001). Higher odds were observed for cough (OR 1.46, p < 0.0001), foreign body sensation (OR 1.1.41, p < 0.001), and voice and resonance disorders (OR 1.19, p = 0.002). Across agents, exenatide, liraglutide, semaglutide, dulaglutide, and lixisenatide showed significant elevated 6-month risk of laryngeal manifestations (OR 1.16-1.91-1.48; p < 0.05), while albiglutide and tirzepatide did not. GLP-1RA/GIP use in adults is linked to higher rates of laryngeal symptoms, most notably cough and voice and resonance disorders. While absolute risk differences were small, the large number of affected individuals underscores the potential clinical and public health relevance of these findings, in the context of the rapidly growing prevalence of GLP-1RA/GIP use.

Type 2 diabetes mellitus (T2D) increases the risk of atherosclerotic diseases, including coronary artery disease (CAD), but decreases that for abdominal aortic aneurysm (AAA), forming an intriguing diabetes-atherosclerosis paradox. We investigate how genetic underpinnings and drug effects shape these complex relationships. A robust positive correlation between T2D and CAD is found throughout the genome, whereas the weak genetic correlation between T2D and AAA is counter-balanced by two-thirds positive and one-third negative correlations. Through single nucleotide variant colocalization, gene annotation, pathway enrichment, and cell type associations, we discover that these positive correlations entail immune responses, whereas the negative correlation is characterized by beta-cell dysfunction and lipid metabolism. Furthermore, the effects of 98 canonical cardiovascular and metabolic drugs are elucidated by pathway pairing and drug-target Mendelian Randomization, revealing that the widely prescribed metformin and glitazones are also protective against atherosclerosis, whereas statins raise the T2D risk. Through screening the plasma proteome against 660 anti-inflammatory drugs, we identify 14 targets and 8 drugs for anti-inflammatory treatments of T2D and atherosclerosis. Our study discovers that both disease-disease and drug-disease interplay contribute to the complex relationships between diabetes and atherosclerosis. Importantly, immune responses synergize with diabetes and atherosclerotic diseases, suggesting anti-inflammatory therapies as a unified treatment strategy.

Osteoporosis is a systemic bone disorder marked by reduced bone mass and deteriorating bone microstructure, commonly associated with inflammation, oxidative stress, and imbalances in immune homeostasis. Among the key mechanisms underlying Osteoporosis progression, disruption of the bone immune microenvironment has emerged as a critical scientific issue. Heat shock proteins (HSPs), as highly conserved molecular chaperones and stress-responsive proteins, not only prevent protein misfolding and aggregation under stress conditions to maintain protein homeostasis, but also participate in immune signaling and adaptive stress responses, thereby playing important roles in preserving bone metabolic homeostasis. This review aims to systematically examine the roles of HSP families-HSPB, HSP40, HSP70, HSP90, and HSP110-in bone remodeling, the balance between osteogenesis and osteoclastogenesis, and the interaction between endoplasmic reticulum stress and mitochondrial energy metabolism. The review also highlights the dual roles of HSPs in regulating bone immune homeostasis. HSPs participate at the cellular level in regulating osteoblast, osteoclast, and bone marrow mesenchymal stem cell function. Current evidence suggests that HSPs act as both molecular chaperones and stress-responsive immune modulators, regulating the balance between bone formation and bone resorption and remodeling the bone immune microenvironment. This review also summarizes HSP-targeted therapeutic strategies, including small molecules, natural products, neutralizing antibodies, physical stimulation, and gene- and cell-based therapies. Research on HSPs is shifting from molecular mechanisms toward precision intervention. Future studies should integrate the "bone-muscle-immune axis" with artificial intelligence and multi-omics technologies to construct a "heat shock response-bone immune" network, identify novel therapeutic targets, and promote personalized prevention and treatment of osteoporosis.

This multicenter retrospective study evaluated the impact of type 2 diabetes mellitus (DM) on clinical outcomes and immune-related adverse events (irAEs) in 450 patients with metastatic non-small cell lung cancer (NSCLC) treated with second-line nivolumab at 17 centers between 2016 and 2024. Among these patients, 118 (26.2%) had DM. Baseline demographic and clinical characteristics, including age, sex, smoking status, ECOG performance status, histology, and PD-L1 expression, were similar between

Toll-like receptor 2 (TLR2) is an innate immune receptor linked to obesity primarily via NF-κB activation. Using a mouse model of overnutrition and in vitro TLR2 stimulation of human peripheral blood mononuclear cells, we show that lipids, advanced glycation end products, and low-density lipoproteins extend TLR2 signaling beyond NF-κB to promote Type I IFN production and signaling, establishing the relevance of this pathway to human obesity. This response was abolished by pharmacologic inhibitio

Psoriasis (PSO) and atopic dermatitis (AD) are the two most common chronic inflammatory skin diseases in clinical practice. For a long time, they have been classified in pathological immunology under the opposing model of "Th17/IL-17 vs. Th2/IL-4-IL-13." However, over the past decade, with the rise of immunometabolism, our understanding of chronic inflammatory diseases has undergone a significant shift. Metabolic pathways in immune cells are no longer viewed merely as auxiliary systems providing