Search Results (310)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as an important class of medications for managing type 2 diabetes and obesity, with cardiovascular outcome trials demonstrating reductions in major adverse cardiovascular events (MACEs) for several agents. The SELECT trial, which enrolled 17,604 participants with established cardiovascular disease and overweight or obesity but without diabetes, showed a 20% reduction in MACEs with semaglutide compared with placebo. Importantly, mediation analyses indicated that weight loss accounted for approximately one-third of this cardiovascular benefit, suggesting that additional mechanisms contribute substantially to the observed risk reduction. The temporal dissociation between weight loss and early MACEs reduction supports the hypothesis that GLP-1RAs exert direct vascular protective effects independent of their metabolic actions. This review synthesizes current evidence on the thromboinflammatory mechanisms through which GLP-1RAs may exert their cardiovascular benefits, with particular emphasis on the neutrophil–NET axis, platelet function, and plaque stabilization. Overall, thromboinflammation represents a biologically reasonable candidate mechanism, but its contribution to the cardiovascular benefit of GLP-1RAs treatment is an open question. Still, residual treatment effects cannot be attributed specifically to thromboinflammation, because metabolic, renal, hemodynamic, and vascular pathways, among others, may also contribute. Full article

Identification of protease cleavage sites is essential for understanding biological regulation and disease mechanisms, yet many predictive approaches rely on annotated substrates and curated databases, limiting performance for poorly characterized proteases. We present PhageScout, a framework for database-independent generation of protease-specific features to predict cleavage sites using de novo experimental substrate phage display screening. We screened a randomized 5-mer phage display library against two neutrophil serine proteases (cathepsin G, elastase). Cleaved peptides generated position weight matrices (PWMs) and peptide enrichment scores to evaluate cleavage-site likelihood across substrate sequences. Sequence-derived scores were integrated with structural features, including accessibility and flexibility, using XGBoost classification models. Performance was benchmarked against annotated cleavage sites from the MEROPS peptidase database as reference data. Phage-derived PWM scores alone captured protease preferences and discriminated cleavage sites from background sites. Without model fitting, PWM scores achieved an area under the curve (AUC) of 0.756 (95%CI: 0.714–0.797) (cathepsin G) and 0.787 (95%CI: 0.753–0.821) (elastase). Combining broad and specific phage-derived scores improved cathepsin G prediction (AUC = 0.783), whereas this improvement was not observed for elastase. Compared to only phage-derived features, XGBoost models integrating phage sequence and structural features provided modest gains for elastase (AUC = 0.775 to 0.806), with phage-derived features ranking among the strongest predictors, but not cathepsin G (AUC = 0.702 to 0.710). Our findings demonstrate that PhageScout can use experimentally derived cleavage signatures to generate protease-specific predictive features and prioritize protease cleavage sites, providing a framework that warrants further validation across diverse proteases and biological contexts. Full article

Background: Atrial fibrillation (AF) is associated with atrial remodelling, hemodynamic stress, and complex cardiopulmonary interactions. While natriuretic peptides and echocardiographic abnormalities are established markers of AF-related substrate, the contribution of spirometry changes, as a landmark of pulmonary impairment, remains less clearly defined. This study evaluated whether AF is associated with an integrated cardiopulmonary profile characterized by altered spirometry, increased NT-proBNP, and conventional echocardiographic markers of left atrial structure and function. Methods: We performed a retrospective, single-center observational study based on an existing clinical database of adult patients referred for 24 h 12-lead Holter ECG monitoring because of palpitations and/or chest pain. None of the included patients had a previously documented diagnosis of atrial fibrillation before Holter monitoring. Because a single 24 h Holter recording cannot establish spontaneous termination or long-term temporal pattern with certainty, AF documented for the first time during this recording is referred to throughout as “newly detected AF” rather than “paroxysmal AF”. During Holter monitoring, no ECG changes suggestive of myocardial ischemia were detected. From 536 records of patients without previously known AF who underwent 24 h 12-lead Holter ECG monitoring for palpitations and/or chest pain, 164 patients were retained for the main comparison, including 48 with newly detected paroxysmal AF and 116 without AF. Demographic, biochemical, spirometric, and echocardiographic variables were analyzed. The main respiratory parameters were forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and peak expiratory flow (PEF). NT-proBNP was the primary biomarker, while conventional left atrial structural and functional variables were used for echocardiographic assessment. Results: NT-proBNP was markedly higher in the AF group (684.5 vs. 62.3 pg/mL, p = 0.001), even when accounting for confounders like age, CKD, or CPD, showing by far the largest between-group difference among the biomarkers assessed (formal discrimination statistics such as ROC/AUC were not computed). The exploratory inflammatory markers assessed (hs-CRP, neutrophil/lymphocyte ratio, homocysteine) showed only modest, non-significant differences. Conventional echocardiographic parameters did not differ significantly between groups. In the strict complete-case comparison, spirometric indices did not reach statistical significance; however, preliminary project-level analysis showed lower FVC, FEV1, and PEF in AF patients, but without supporting the COPD diagnosis, and exploratory correlations suggested a relationship between spirometric performance and left atrial function. Conclusions: In this cohort, AF was most strongly associated with NT-proBNP, while the respiratory signal was weaker but directionally consistent with a broader cardiopulmonary phenotype. These findings do not support spirometry or NT-proBNP as stand-alone diagnostic tools for AF. However, when interpreted alongside traditional AF risk factors and symptoms, elevated NT-proBNP with concordant spirometric impairment may represent a hypothesis-generating additive signal supporting longer or repeated rhythm monitoring beyond 24 h in selected patients with suspected AF; this additive value was not formally tested against clinical models alone and requires prospective confirmation. Full article

The kallikrein–kinin system (KKS) and the kallikrein-related peptidase (KLK) family are interconnected proteolytic networks that regulate inflammatory signaling, vascular permeability, extracellular matrix remodeling, and tissue barrier dynamics. Beyond their classical vasoactive and inflammatory functions, accumulating evidence indicates that kinin peptides, including bradykinin, Lys-bradykinin, and their des-Arg⁹ metabolites, together with selected KLKs, modulate cell–cell and cell–extracellular matrix adhesion. Through B1 and B2 kinin receptor activation, the KKS influences endothelial adhesion molecule expression, leukocyte integrin activation, neutrophil trafficking, focal adhesion kinase/Src signaling, cytoskeletal remodeling, and matrix metalloproteinase activity. In parallel, KLKs directly reshape the adhesive microenvironment by cleaving junctional proteins, including E-cadherin and desmosomal components, and extracellular matrix substrates such as fibronectin, laminin, vitronectin, fibrinogen, and collagens. These coordinated actions affect epithelial and endothelial barrier integrity, leukocyte transmigration, angiogenesis, fibrosis, epithelial–mesenchymal transition, tumor cell migration, invasion, and metastatic dissemination. This review critically summarizes current evidence linking KKS and KLK activity to adhesion-dependent processes in inflammation and cancer, emphasizing how proteolytic signaling may either preserve tissue homeostasis or promote pathological barrier disruption depending on cellular context, receptor expression, protease activity, and microenvironmental cues. Understanding these mechanisms may refine the identification of adhesion-related biomarkers and support the development of targeted therapeutic strategies for inflammatory disorders, fibrotic remodeling, and cancer progression. Full article

Background/Objectives: DEFA3 and DEFA5 are alpha-defensins, which are small cationic antimicrobial peptides that are part of the innate immune system. DEFA3 encodes human neutrophil peptide-3 (HNP-3), primarily expressed in neutrophils, while DEFA5 encodes human defensin-5 (HD-5), predominantly expressed in Paneth cells of the small intestine. Both defensins show elevated levels in diabetes and are strongly associated with diabetic nephropathy, with the highest concentrations found in patients with this complication. We evaluated serum levels of DEFA3 and DEFA5 in 160 participants (93 patients with T2DM and 67 controls without carbohydrate disturbances) and their associations with diabetic nephropathy, as well as peripheral and cardiac autonomic neuropathy and anthropometric and metabolic parameters. Methods: This was a monocentric, cross-sectional, observational study conducted at the Endocrinology and Metabolic Disorders Clinic of Alexandrovska Hospital in Sofia. Main methods included detailed clinical and anthropometric assessments, diagnosis of peripheral neuropathy via the Neuropathy Disability Score (NDS), evaluation of cardiac autonomic neuropathy using heart rate variability analysis and Ewing cardiovascular reflex tests, comprehensive laboratory investigations with fasting blood samples, and measurement of serum DEFA3 and DEFA5 levels by ELISA kits. Results: Serum DEFA3 and DEFA5 levels did not differ significantly between patients with T2DM and controls without carbohydrate disturbances, nor by sex or menopausal status. Patients with diabetic nephropathy showed significantly higher levels of both DEFA3 (345.7 ± 77.9 pg/mL vs. 299.2 ± 100.3 pg/mL; p = 0.042) and DEFA5 (5.3 ± 10.1 pg/mL vs. 2.9 ± 2.9 pg/mL; p = 0.044). DEFA5 levels were also elevated in participants with increased albumin-to-creatinine ratio (4.9 ± 9.9 pg/mL vs. 2.2 ± 1.5 pg/mL; p = 0.043). No significant differences were observed in patients with peripheral neuropathy, cardiac autonomic neuropathy, retinopathy, or macroangiopathy, although a non-significant trend toward higher values was noted. DEFA3 demonstrated moderate discriminatory ability for diabetic nephropathy (AUC = 0.641; p = 0.037), superior to DEFA5 (AUC = 0.570; p = 0.303). DEFA3 showed multiple weak positive correlations with diabetes duration, body weight, BMI, total and LDL-cholesterol, serum creatinine, and uric acid, while DEFA5 correlated only with total cholesterol. Conclusions: Circulating DEFA3 and DEFA5 are associated with diabetic nephropathy and selected metabolic and renal parameters in patients with type 2 diabetes, with DEFA3 showing moderate discriminatory capacity. The associations were largely attenuated after covariate adjustment, suggesting that these alpha-defensins likely reflect downstream innate immune activation and renal stress rather than acting as independent drivers of complications. Full article

Background/Objective: Obesity has been linked to a distinct non-allergic, late-onset, neutrophilic asthma phenotype for more than two decades, yet whether obesity should be regarded as a cause of that phenotype rather than a coexisting comorbidity remains unresolved because randomised allocation to obesity is neither feasible nor ethical. This review asks whether the evidence accumulated between 1995 and 2026 supports a causal interpretation. Methods: A structured narrative synthesis was undertaken. PubMed/MEDLINE, Scopus and Web of Science were searched from January 1995 to June 2026 (the synthesis emphasises the 2020–2026 evidence while drawing on the full window for landmark studies) for cohort, cross-sectional, Mendelian randomisation (MR), interventional, mechanistic and pharmaco-epidemiological studies; landmark earlier work was retained where it remains the primary source for a given viewpoint. The retrieved evidence was mapped onto Sir Austin Bradford Hill’s nine viewpoints (1965) and triangulated using E-values for unmeasured confounding, GRADE, directed acyclic graphs and MR. Results: All nine viewpoints were satisfied to varying degrees. Strength: effect estimates 1.4–6.8, E-values 4.8–13.1, MR summary risk ratio 1.05 per 1 kg/m². Consistency: replication across four continents, both sexes and multiple study designs. Temporality: prospective cohort and life-course MR evidence. Biological gradient: body mass index dose–response for TNFα, IL-17A and Th17 frequency. Plausibility: a twelve-layer architecture from adipose dysfunction to bronchial epithelium. Coherence, experimental evidence (bariatric surgery, lifestyle weight loss, GLP-1 receptor agonists, murine and in vitro models) and analogy were also supported; specificity was met at the phenotype level. Conclusions: The cumulative evidence strongly supports a causal contribution of obesity to the development of the late-onset, non-allergic asthma phenotype while falling short of definitive proof (GRADE: moderate certainty), with implications for primary prevention, endotype-targeted therapy and longitudinal research. Phenotype-stratified MR remains the principal missing element of the causal argument. Full article

Tuberculosis (TB) and chronic obstructive pulmonary disease (COPD) remain global public health challenges, yet the mechanisms underlying their comorbidity remain poorly understood. COPD is associated with an increased risk of active TB, but the cellular and molecular basis of this association remains unclear. A growing body of evidence suggests that TB is not limited to an intramacrophage infection but is accompanied by a disruption of the local immune balance in lung tissue. This review analyzes the early interface of host–Mycobacterium tuberculosis (Mtb) interaction—from pattern recognition signaling pathways and metabolic reprogramming of macrophages to epithelial barrier responses and the delayed αβ T cell response. This review evaluates γδ T cells, particularly phosphoantigen (pAg)-reactive Vγ9Vδ2 cells, as a candidate early integrative component of the host response, positioned between macrophage infection, epithelial stress, mycobacterial antigens, and bacille Calmette–Guérin (BCG)-induced trained immunity. Available evidence suggests that COPD-associated immune alterations may impair mucociliary clearance, antimicrobial peptide production, phagocytosis, and innate T cell responses while favoring cytotoxic reactions, the IL-17A–G-CSF–neutrophil axis, and protease-mediated tissue damage; however, direct mechanistic evidence in patients with TB–COPD remains limited. It is important to note the differences in data obtained from studies in humans, primates, mice, and in vitro: the Vγ9Vδ2 system has no direct analog in laboratory mice, which represents a key limitation for preclinical studies. A key unresolved question remains the nature and functional consequences of γδ T cell changes in patients with coexisting COPD and TB infection. The answer to this question could inform new strategies for the prevention and treatment of TB in patients with COPD, including BCG revaccination, pAg-mediated immunomodulation, and the development of biomarkers to distinguish between protective and harmful early immune responses. Full article

Background/Objectives: Inflammatory and metabolic abnormalities are common in patients hospitalized with heart failure (HF), particularly during episodes of decompensation. Their associations with short-term in-hospital outcomes remain incompletely understood. Methods: We retrospectively reviewed 499 patients with documented chronic HF who were admitted for acute medical conditions between January and May 2024. The cohort was not limited to patients admitted for HF exacerbation; patients were classified as having compensated or decompensated HF at admission. Body mass index (BMI) was available for 498 patients, whereas HF status at admission was available for all 499 patients. Clinical, metabolic, and laboratory parameters were analyzed, with particular attention to C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune–inflammation index (SII), and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were stratified according to BMI category (<25 kg/m² or ≥25 kg/m²) and HF status at admission. Associations with all-cause in-hospital mortality were evaluated using multivariable logistic regression analysis. Results: Patients with decompensated HF at admission had higher CRP, NLR, PLR, SII, and NT-proBNP levels, as well as lower hemoglobin and eGFR values. All-cause in-hospital mortality was numerically higher in patients with BMI < 25 kg/m² than in those with BMI ≥ 25 kg/m² (8.4% vs. 4.2%), but the difference was not statistically significant (Pearson’s χ² test, p = 0.063). In adjusted analyses, CRP and SII were associated with all-cause in-hospital mortality, whereas NT-proBNP was not. Patients with higher BMI more often had glycemic and lipid abnormalities, whereas those with lower BMI had a more pronounced inflammatory profile. The apparent area under the curve (AUC) values were 0.793 for the CRP-based model and 0.814 for the SII-based model; after bootstrap correction, the optimism-corrected AUC values were 0.729 and 0.754, respectively. Conclusions: Higher CRP and SII levels were associated with all-cause in-hospital mortality after adjustment for selected clinical variables. Full article

Background/Objectives: The human cathelicidin LL-37 (37 residues; net charge +6) couples broad-spectrum antimicrobial activity with immunomodulatory function, but rapid proteolysis and peptidylarginine deiminase (PAD)-mediated citrullination limit its therapeutic use. We aimed to enhance enzymatic stability and to test whether substitution with 2,3-diaminopropionic acid (Dap) building blocks bearing an oxa-acid spacer (DAPEG) shifts the functional profile of the LL-37 scaffold. Methods: Six LL-37 analogs were synthesized using Fmoc/tBu solid-phase peptide synthesis, replacing all five arginine, all six lysine, or three isoleucine residues with Dap bearing a one- or two-unit oxa-acid spacer. Identity, purity and secondary structure were assessed via mass spectrometry, ultra-performance liquid chromatography and circular dichroism. Proteolytic stability against human proteinase 3 (PR3), resistance to PAD2/PAD4 citrullination, DNA binding (dynamic light scattering), antibacterial activity, MTT cytotoxicity, and lipopolysaccharide-induced degranulation (PR3 and myeloperoxidase) in differentiated HL-60 cells were evaluated. Results: Proteolytic stability against PR3 increased 5.7-fold for the arginine-substituted Dap(GO1) analog, and both arginine analogs resisted PAD2- and PAD4-mediated citrullination, with Dap(GO2) being the most resistant. DNA binding was qualitatively retained, although dynamic light scattering showed weaker complex compaction for lysine analogs. All six analogs lost direct antibacterial activity and were non-cytotoxic at 1–10 µM. In differentiated HL-60 cells, the lysine-substituted Dap(O1) and Dap(O2) analogs suppressed lipopolysaccharide-induced secretion of both PR3 and myeloperoxidase from azurophilic granules, whereas isoleucine analogs were suppressed partially and arginine analogs behaved like native LL-37. Conclusions: The DAPEG framework shifts LL-37 from microbicidal toward degranulation-suppressive activity, providing a modular route to tune cathelicidin function. The intracellular mechanism (TLR4/FPR2 engagement, cytokine signaling) was not assayed. Full article

LL-37 has attracted significant research attention as a multifunctional antimicrobial peptide which is implicated in a broad spectrum of activities. It is the only human cathelicidin and represents a key molecule in host defense. Hence, it is described as possessing antimicrobial activity against a wide range of pathogens, including Gram-negative and Gram-positive bacteria, numerous viral species, and various fungi. Though it is widely recognized for its direct antimicrobial activity, it is a multifaceted immunomodulatory and tissue-protective molecule. Beyond host defense, LL-37 actively regulates inflammatory signaling, cellular interactions within the immune system, and mechanisms of tissue repair. Its ability to fine-tune immune responses and simultaneous regeneration highlights its dual role in inflammation control and wound healing. These pleiotropic functions place LL-37 in the spotlight between innate immunity and tissue homeostasis. This review aims to compile LL-37’s antimicrobial and immunomodulatory activities and highlight its wide range of potential clinical applications. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine. Full article

Cardiorenal Syndrome (CRS) types depend on the primary impaired organ, Heart (Types I/II) or Kidney (Types III/IV), and are chronic (Types II/IV) or acute (Types I/III). Type V associates to a systemic disease. Diagnosis of CRS type via biochemical indices (e.g., B-type-natriuretic-peptide (BNP), neutrophil-gelatinase-associated-lipocalin (NGAL)) has not been documented absolutely, until now. Here we used advanced imaging facilities, atomic force microscope (AFM) and scanning electron microscope (SEM) for the biopsy of peripheral blood smears coming from CRS patients, aiming to investigate the possible existence of cellular indices associated with CRS pathology. Standard biochemical and hematological indices were comparatively recorded. Cylindrical micro/nano-metric Vesicles (mnVs) were observed in all CRS patients. In CRS patients with Types III/IV, the AFM/SEM data revealed an increased mnVs population and activated platelets that may represent their potential parent cells. In these patients, increased basic uraemic indices and BNP and NGAL levels were also observed. On the contrary, in patients with CRS Types I/II/V, the AFM/SEM data showed a comparatively smaller mnVs population, accompanied by lower levels of BNP and NGAL. According to our results, a higher mnVs population was observed in CRS Types III/IV, possibly released from platelets. The mnVs population may be associated with basic uraemic indices and increased BNP and NGAL levels. Full article

Systemic antibiotics are among the most widely prescribed therapeutic agents worldwide, and their effects on host–microbe equilibrium extend well beyond the infection for which they are intended. Periodontitis is conventionally framed as a biofilm-initiated, host-mediated inflammatory disease, although recent work has shifted this framework toward microbial homeostasis as a regulator of periodontal stability. We hypothesize that antibiotics are not direct etiologic agents of periodontitis but instead act as risk-modifying factors that lower the threshold at which plaque-mediated inflammation progresses to destructive disease. We propose that this effect may operate through several mechanisms: broad-spectrum or repeated exposure could deplete protective commensals and narrow microbial diversity, creating ecological space for opportunistic and pathogenic taxa; antibiotics may also alter host neutrophil function, cytokine profiles, and antimicrobial peptide regulation and may interfere with the osteoblastic and osteoclastic dynamics governing alveolar bone remodelling; and antibiotic-induced gut dysbiosis may propagate systemic inflammatory signals that further modulate periodontal susceptibility. To evaluate this hypothesis, we synthesize the available clinical, epidemiological, and experimental data across four converging axes—oral microbial ecology, immune regulation, alveolar bone remodelling, and the gut–oral axis—and identify the predictions the hypothesis generates and the evidence gaps it exposes. We emphasize that no clinical study has yet demonstrated a causal link between antibiotic exposure and periodontitis; the framework advanced here is therefore intended to inform antimicrobial stewardship in dentistry and to define a research agenda for determining whether antibiotic exposure constitutes a clinically meaningful modifier of periodontal disease susceptibility. Full article

Alveolar echinococcosis is a life-threatening zoonotic parasitic disease caused by infection of Echinococcus multilocularis larvae. To survive within the host’s immune milieu, E. multilocularis has evolved sophisticated immune evasion strategies, including the expression of immunomodulatory proteins that regulate the host immune response. Our previous studies have demonstrated that E. multilocularis calreticulin (EmCRT) possessed strong binding ability to human complement component C1q to inhibit C1q-initiated complement activation and biological functions. To further elucidate the mechanism by which EmCRT mediates C1q inactivation and immune evasion, the precise C1q-binding site on EmCRT was identified and analyzed in this study through expression of overlapping fragments and synthesis of overlapping peptides covering the identified functional fragment. The fragment expression and functional assay narrowed down the C1q-binding site to the EmCRT-S1 fragment located between amino acids 140 and 204 of EmCRT. The precise binding site was further pinpointed to the P5 peptide (EmCRT160–174 aa) by testing the synthetic peptides covering this region. The binding of peptide P5 to C1q markedly suppressed the activation of the C1q-mediated classical complement pathway and C1q-induced neutrophil chemotaxis, production of reactive oxygen species, cathepsin G, and myeloperoxidase. These findings suggest that the C1q-binding P5 peptide of EmCRT may serve as a potential target for the development of vaccines against echinococcosis or therapeutic drugs for complement-associated inflammatory or autoimmune diseases. Full article

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on clinical, genetic, and molecular predictors of tirzepatide response and discuss their implications for a precision medicine framework. Data from pivotal clinical trials, post hoc analyses, and relevant preclinical and clinical studies were evaluated to identify determinants of glycemic and weight loss responses, as well as hepatic and renal protective effects. Key clinical predictors include tirzepatide dose, duration of diabetes, β-cell function, baseline glycated hemoglobin, sex, age, race, concomitant therapies, and early treatment response. Genetic factors implicated in treatment variability include variants in GLP-1 receptor, GIP receptor, β-arrestin 1, transcription factor 7-like 2, fat mass and obesity-associated protein, and melanocortin 4 receptor, although tirzepatide-specific validation remains limited. Molecular biomarkers such as branched-chain amino acids, insulin-like growth factor–binding protein-1 and -2, the adiponectin-to-leptin ratio, high-sensitivity C-reactive protein, and interleukin-6 show potential as pharmacodynamic indicators of metabolic response. For organ-specific outcomes, procollagen type III N-terminal peptide and magnetic resonance imaging–proton density fat fraction are supported for assessing hepatoprotective effects, while cystatin C–based estimated glomerular filtration rate and urine albumin-to-creatinine ratio are validated markers of renoprotection. Additional candidates—including tumor necrosis factor receptor 1/2, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin—are promising but require prospective validation. Overall, predicting response to tirzepatide’s multifaceted therapeutic effects necessitates an integrated, multidimensional approach that incorporates clinical characteristics, genetic variation, and molecular profiling. Ongoing validation and harmonization of these predictors may help establish a precision medicine framework for optimizing tirzepatide therapy. Full article