Search Results (11,449)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease with a complex pathogenesis that significantly affects patients’ quality of life. Type 2 inflammation plays a dominant role in its course and is associated with the activation of immune pathways involving interleukins IL-4, IL-5 and IL-13, eosinophils, and immunoglobulin E. Standard treatment methods, including corticosteroids and surgical interventions, despite their proven efficacy, often fail to provide sustained disease control and are associated with a high rate of recurrence. The aim of this review is not only to summarize the available evidence on biological therapies in CRSwNP, but also to critically evaluate their current position within treatment algorithms, with particular emphasis on patient selection, integration with endoscopic sinus surgery, comparison of available biologic mechanisms, and remaining challenges in personalized treatment strategies. The paper discusses available monoclonal antibodies, such as dupilumab, omalizumab, mepolizumab, and benralizumab, which act by selectively inhibiting key mediators of type 2 inflammation. Analysis of clinical trial results indicates that biological therapies lead to a significant reduction in nasal polyp size, improvement in nasal patency, restoration of olfactory function, and enhancement of quality of life as measured by the SNOT-22 scale. Furthermore, they demonstrate a favourable safety profile and may represent an effective therapeutic option for patients with severe, treatment-resistant disease, particularly in cases with coexisting eosinophilic asthma. Biological therapies represent a breakthrough in the treatment of CRSwNP and align with the concept of personalised medicine. Their role in clinical practice continues to expand; however, further research is required to optimise patient selection and assess long-term treatment outcomes. Full article

Background: Evidence regarding the impacts of magnesium (Mg) supplementation on cardiometabolic risk factors (CMRFs) remains inconsistent. Objectives: This systematic review and dose–response meta-analysis evaluated effects of Mg supplementation on anthropometric indices, liver and kidney function, lipid and glycemic profiles, blood pressure, and inflammatory biomarkers. Methods: A systematic search of electronic databases up to May 2026 identified 78 eligible randomized controlled trials. Results: Mg supplementation significantly reduced body weight (weighted mean difference [WMD]: −0.70 kg; 95% confidence interval [CI]: −1.30, −0.09), diastolic blood pressure (WMD: −1.58 mmHg; 95% CI: −2.50, −0.65), homeostasis model assessment of insulin resistance (WMD: −0.48; 95% CI: −0.79, −0.18), low-density lipoprotein cholesterol (WMD: −3.21 mg/dL; 95% CI: −5.27, −1.15), fasting blood glucose (WMD: −3.60 mg/dL; 95% CI: −6.13, −1.06), systolic blood pressure (WMD: −2.50 mmHg; 95% CI: −4.08, −0.91), glycated hemoglobin (WMD: −0.15%; 95% CI: −0.26, −0.03), triglycerides (WMD: −9.24 mg/dL; 95% CI: −16.87, −1.61), and interleukin-6 levels (WMD: −1.10 pg/mL; 95% CI: −1.93, −0.27) compared with controls. High-density lipoprotein cholesterol concentrations significantly increased (WMD: 1.45 mg/dL; 95% CI: 0.37, 2.54). No significant effects were identified on hip circumference, alanine aminotransferase, waist circumference, tumor necrosis factor-α, creatinine, C-reactive protein, body mass index, total cholesterol, fasting insulin, body fat percentage, and aspartate aminotransferase. Most RCTs (79.5%) administered Mg doses ≥ 300 mg/day, and 66.7% had intervention durations ≥ 12 weeks; however, evidence from higher-dose (≥500 mg/day) and longer-term (≥25 weeks) interventions remained limited. Conclusions: Mg supplementation was associated with significant improvements in several CMRFs, including body weight, lipid and glycemic profiles, blood pressure, and interleukin-6 levels. However, these effects were generally modest, and their clinical relevance remains uncertain given the variable certainty of evidence across outcomes. Full article

Immunobiologics or biologics have revolutionized the therapeutic paradigm of autoimmune and inflammatory diseases by selectively targeting and modulating dysregulated immune pathways. Compared with conventional broad-spectrum immunosuppressants, biologics provide a more specific and mechanism-based rational approach, often associated with improved efficacy and reduced adverse events. This review provides a comprehensive overview of the repertoire of therapeutic biologics, their mechanisms of action, pivotal clinical trials, and clinical applications. We discuss biologics targeting T-cell activation, depletion, and adhesion, as well as agents neutralizing pro-inflammatory cytokines, including tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, IL-12, IL-17, IL-22, and IL-23, in addition to B-cell-directed therapies and IgE-modulating agents. Evidence from randomized clinical trials and observational studies highlights the profound therapeutic impact of these agents across a broad spectrum of immune-mediated diseases, including rheumatoid arthritis, psoriasis, systemic lupus erythematosus (SLE), ankylosing spondylitis, chronic spontaneous urticaria, asthma, ulcerative colitis, Crohn’s disease, and other forms of inflammatory bowel disease (IBD). Pharmacodynamic parameters, including receptor-binding affinity and downstream pathway modulation, are critical determinants of therapeutic efficacy, whereas pharmacovigilance remains indispensable for monitoring risks such as immunogenicity, opportunistic infections, and manufacturing-related variability. Continuous regulatory oversight by agencies such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) safeguards standards of safety, efficacy, and quality. In parallel, the expanding development of biosimilars offers a key opportunity to enhance affordability and broaden global access to biologic therapies. Despite substantial clinical progress, important challenges persist, including disease heterogeneity, variability in therapeutic response, long-term safety concerns, and issues of cost-effectiveness. Future directions emphasize precision medicine strategies, including biomarker-guided treatment, rationally designed biologic combinations, next-generation antibody engineering, and the development of high-quality biosimilars to improve therapeutic durability, safety, and accessibility equity. By integrating mechanistic insights with clinical outcomes, this review underscores the transformative role of immunobiologics and delineates strategies to optimize their application in the management of autoimmune and inflammatory diseases. Full article

Background: Blood-accessible biomarkers may support future personalization of prostate cancer radiotherapy, but their interpretation depends on sampling timing relative to radiotherapy, androgen deprivation therapy, and post-treatment recovery. We mapped clinical evidence for selected biomarker domains beyond prostate-specific antigen: γ-H2AX/DNA damage response, IL-6/inflammatory mediators, testosterone/endocrine recovery and a prespecified galectin-1/3 immune–stromal domain evaluated as a potential evidence gap. Methods: We conducted a PRISMA-ScR scoping review of PubMed, Scopus, and Web of Science searched on 7 January 2026. Eligible original human studies evaluated soluble serum/plasma analytes or peripheral blood cell-based assays in prostate RT pathways. Data were charted by biomarker domain, treatment context, RT modality/fractionation, assay reporting, sampling schedule, and endpoint linkage. Results: Of 3499 records, 45 studies were included. No eligible study reported repeated circulating galectin-1/3 kinetics anchored to prostate radiotherapy, identifying a distinct clinical evidence gap. The remaining evidence was dominated by testosterone studies (n = 28), followed by IL-6/inflammatory mediators (n = 12) and γ-H2AX/DDR (n = 5). Testosterone studies were mapped as separate RT-only endocrine kinetics and ADT-anchored recovery streams. IL-6 studies mainly used during-RT or early post-RT sampling and linked trajectories to acute toxicity, fatigue, symptoms or inflammatory phenotypes; no included study directly validated serial IL-6/inflammatory trajectories against biochemical control, metastasis-free survival, or overall survival. γ-H2AX studies were characterized by ultra-acute, fraction-anchored sampling. Across domains, baseline definition and sampling timing limited interpretability more than assay platform alone. Conclusions: Evidence maturity was unequal across the selected domains. Testosterone provided the comparatively more developed longitudinal clinical literature, whereas IL-6/inflammatory mediators remained exploratory and were linked mainly to acute toxicity, fatigue, symptoms, and inflammatory phenotypes. γ-H2AX remained predominantly a translational and biodosimetry-oriented marker, while galectin-1/3 represented a hypothesis-generating clinical evidence gap. None of these biomarkers currently supports routine biomarker-guided prostate RT personalization. Future biomarker-embedded studies may benefit from domain-specific sampling considerations, explicit RT/systemic-therapy context stratification, standardized assay reporting, and clinically relevant endpoints. Full article

Atherosclerotic cardiovascular disease (CVD) remains a leading cause of worldwide morbidity and mortality, despite well-established/effective pharmacological therapies. A substantial component of the residual risk is inflammatory. The importance of inflammation and immune mediators in the pathophysiology has been recognised over the past two decades and, importantly, treatment with percutaneous coronary intervention (PCI) also results in an inflammatory response and associated adverse outcomes. Multiple biochemical pathways have been implicated with various identified biomarkers, such as high-sensitivity C-reactive protein which is now recognised as a marker of cardiovascular risk. Proteins such as interleukins (IL) IL-1 and IL-6 or larger protein complexes such as the NLRP3 inflammasome all play a key role in both the pathophysiology of atherosclerosis and inflammation relating to PCI. This knowledge has led to advances in pharmacological therapies and multiple pre-clinical and clinical trials, but to date, colchicine is the only treatment with sufficiently robust evidence from large-scale clinical trials to be recommended in multinational guidelines. Other therapies at present lack this level of evidence, and identification of other potential therapies is an important next step in treating inflammation post-PCI. Furthermore, the potential routine use of colchicine periprocedurally for PCI and its biochemical and clinical effects in this context are not yet fully established, requiring further investigation to identify its effect on specific inflammatory mediators and whether this translates to clinical outcomes. Full article

Background/Objectives: This study aimed to identify common target genes, molecular interaction networks, and signaling pathways shared across the investigated toxic metal(loid)s—lead (Pb), cadmium (Cd), methylmercury compounds (MMC), arsenic (As), nickel (Ni), and hexavalent chromium (Cr(VI))—and associated with lung cancer overall, non-small-cell lung cancer (NSCLC), and small-cell lung cancer (SCLC). Methods: The Comparative Toxicogenomics Database (CTD) was used to identify associated genes, GeneMANIA to characterize molecular interaction networks, and ToppFun for pathway enrichment analysis. Results: Two common genes (MTOR and TP53) were identified for SCLC, eight for NSCLC (CAT, CCNB1, MTOR, NQO1, SOD2, STAT3, TP53, and VEGFA), and eighteen for lung cancer overall. Gene network analysis revealed predominantly physical interactions in SCLC, pathway interactions in NSCLC, and co-expression in lung cancer overall. Several toxic metal(loid)s exhibited concordant effects on TP53, VEGFA, HMOX1, and IL6 expression. TP53 was the only gene common to all investigated toxic metal(loid)s and lung cancer categories. Pathway enrichment identified PI3K–AKT–mTOR signaling in both SCLC and NSCLC, VEGF signaling in NSCLC, and MAPK, interleukin, and macrophage-stimulating protein (MSP) signaling in lung cancer overall. Conclusions: The identified genes and pathways suggest molecular mechanisms potentially relevant to the association between exposure to the investigated toxic metal(loid)s and lung carcinogenesis, particularly those related to cell survival, inflammation, oxidative stress, and angiogenesis. TP53 may represent a common molecular link warranting further investigation. The identified pathways represent candidate biomarkers and mechanistic targets, highlighting the biological heterogeneity of lung cancer and the importance of subtype-specific analyses. Full article

The rapid expansion of biologic therapies for immune-mediated inflammatory diseases has raised significant clinical concerns regarding malignancy risk, particularly for patients with a history of cancer. This narrative review explores the safety of targeted therapies across dermatology, rheumatology, respiratory medicine, and gastroenterology to guide clinicians in these therapeutic dilemmas. We conducted a non-systematic review of the literature, prioritising longitudinal registry and real-world cohort data over clinical trials to better capture malignancy outcomes with long latency periods. Results indicate that tumour necrosis factor (TNF) inhibitors, which have the most extensive evidence base, do not consistently demonstrate an increased risk of overall incident malignancy or recurrence across specialties. Newer agents, including interleukin (IL)-17 and IL-23 inhibitors, show reassuring safety profiles in both trial and registry data. While dupilumab is associated with the potential diagnostic ‘unmasking’ of pre-existing cutaneous T-cell lymphoma, overall cancer rates remain stable among users. Most clinical guidelines support an individualised, multidisciplinary approach involving oncology consultation. We conclude that biologic agents can be used cautiously in certain patients with a history of malignancy following multidisciplinary discussion; however, in those with active malignancy there are no meaningful data that exist. Most evidence is heterogenous and excludes patients with a history of malignancy. Future management requires validated decision frameworks and mandatory participation in real-world patient co-created registries which leverage developing artificial intelligence tools to refine long-term safety assessments. Full article

Residual inflammation remains a hallmark of treated HIV infection despite durable viral suppression. Whether previous SARS-CoV-2 infection is associated with residual inflammation in people living with HIV (PLWH) remains incompletely understood. This study evaluated the association between previous COVID-19 and persistent inflammation in virally suppressed PLWH. In this retrospective observational single-center study, 286 adults receiving antiretroviral therapy between January 2023 and December 2025 were included. Patients were stratified according to documented SARS-CoV-2 infection history. A secondary analysis included 231 individuals with sustained viral suppression (HIV-RNA < 50 copies/mL). Inflammatory biomarkers, immune recovery parameters, metabolic characteristics, and independent predictors of elevated inflammatory biomarker levels were evaluated. Previous SARS-CoV-2 infection was associated with significantly higher concentrations of C-reactive protein, interleukin-6, tumor necrosis factor-α, erythrocyte sedimentation rate, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (all p< 0.01). Among virally suppressed patients, elevated inflammatory biomarker levels were associated with lower CD4+ T-cell counts, lower CD4/CD8 ratios, obesity, metabolic syndrome, dyslipidemia, and hepatic steatosis. Previous SARS-CoV-2 infection, obesity, metabolic syndrome, and CD4+ T-cell counts <500 cells/mm³ were independently associated with elevated inflammatory biomarker levels. Previous SARS-CoV-2 infection was independently associated with an unfavorable inflammatory profile in virally suppressed people living with HIV. Given the retrospective observational design, these findings should be interpreted as associations rather than evidence of causality. These findings suggest that long-term host-related and metabolic factors may contribute to residual inflammation beyond viral control and highlight the need for prospective studies investigating strategies to reduce residual immune activation in treated HIV infection. Full article

In postmortem Alzheimer’s disease (AD) brains, Porphyromonas gingivalis (Pg), a major periodontal pathogen, and Candida albicans, one of the most common fungal pathogens, have been detected. Although it is important to better understand the effects of their co-infection in the brain for elucidating the pathogenesis of AD, little is known about the neuropathological significance of such co-infection. In the present study, we aimed to elucidate the effects of co-exposure to virulence factors derived from Pg and C. albicans on microglial inflammatory responses. We demonstrated, for the first time, that both candidalysin dissolved in dimethyl sulfoxide (CLd) and water (CLw) significantly suppressed Pg lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) production by 35–60% and nuclear factor-κB (NF-κB) activation by 20–40%. It should be noted that contaminating Pg outer membrane lipoproteins in Pg LPS were mainly responsible for IL-1β production. To examine the possible hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL, we used 8-anilino-1-naphthalenesulfonic acid sodium salt (ANS-Na), which can be excited to emit fluorescence by binding of hydrophobic molecules. The mean fluorescence intensity of ANS-Na was significantly reduced by approximately 26% following co-treatment with CLw and Pg LPS compared with CLw alone. Furthermore, we generated a mutant form of CL with reduced hydrophobicity (GRAVY index: 1.106 vs. 0.874) while preserving its predicted structural properties. This mutant CLd no longer inhibited Pg LPS-induced IL-1β production. Taken together, these findings indicate that hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL mediate the inhibitory effect of CL on Pg LPS-induced inflammatory responses. The present findings suggest that interactions between polymicrobial virulence factors in the brain may modulate microglia-mediated inflammatory responses during AD progression. Full article

Background: Autoimmune diseases (AIDs) are associated with increased cardiovascular risk. However, specific protein mediators linking AIDs to major adverse cardiovascular events (MACE) and cardiovascular death (CV death) remain unexplored. This study identifies proteomic mediators linking AIDs to MACE via high-dimensional mediation analysis in the UK Biobank. Methods: We used UK Biobank data with proteomic profiling by Olink platform. Participants with prevalent myocardial infarction (MI), stroke, and heart failure at baseline were excluded. AIDs were categorized into musculoskeletal (MSK), vasculitis, gastrointestinal (GI), neurologic, and rheumatic fever subsets. Fine–Gray models assessed associations between AIDs and MACE and CV death. Proteome-wide association studies identified proteins associated with both AIDs and cardiovascular outcomes. High-dimensional mediation analysis (HIMA) explored protein-mediated pathways. All models adjusted for age, sex, lipids, BMI, smoking, hypertension, diabetes, chronic kidney disease, atrial fibrillation, and coronary artery disease. Results: Among 400,633 participants (median follow-up 14.5 years, 44.8% male), AIDs were present in 28,754 (7.2%). All AID categories were associated with increased MACE (sHR: MSK 1.34, vasculitis 1.67, GI 1.20, neurologic 1.33, rheumatic fever 1.38; all p < 0.001). For CV death, MSK, vasculitis, and rheumatic fever showed increased risk (sHR 1.34, 1.78, 1.51; all p ≤ 0.004), but not GI or neurologic AIDs. In 43,599 participants with proteomic data, HIMA identified 66 and 32 unique potential mediators linking AIDs to MACE and CV death, respectively. Four proteins (Growth Differentiation Factor 15, Interleukin-15, urokinase plasminogen activator receptor, and Tenascin C) mediated the AID-MACE relationship across multiple AID categories. Growth Differentiation Factor 15 and Interleukin-15 were shared mediators for CV death. Conclusions: This proteomic analysis identifies specific proteins that may mediate the association between AIDs and adverse cardiovascular outcomes, offering mechanistic insights into immune-related cardiovascular risk. These findings are hypothesis-generating and require replication and validation before the identified proteins can be considered causal mediators or adopted for clinical risk stratification. Full article

Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are typically produced in a 3:1:1 ratio, respectively, via microbial fermentation of non-digestible carbohydrates, and to a lesser degree, from undigested protein. The effects of individual SCFAs on adipocyte function have been described; however, the effects of SCFAs in combination on adipocyte function remain unknown. Mature 3T3-L1 adipocytes were treated with a 1 mM total dose of acetate, propionate, and butyrate combined in a 3:1:1 ratio, respectively, for 24 h ± lipopolysaccharide (LPS, 10 ng/mL) under both normoxic and hypoxic (via the addition of 100 µM cobalt chloride) environmental conditions. In both normoxic and hypoxic LPS-stimulated conditions, SCFAs increased the secretion of adiponectin and reduced the secretion of resistin, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1/C-C motif chemokine ligand (CCL)2, and RANTES/CCL5, in addition to reducing intracellular protein levels of activated (i.e., the ratio of phosphorylated-to-total) nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) p65 and signal transducer and activator of transcription 3 (STAT3) (p < 0.05). Additionally, SCFA treatment reduced leptin secretion only in LPS-stimulated normoxic environmental conditions compared to control (p < 0.05). In normoxic conditions, SCFA + LPS increased mRNA expression of genes involved in fat storage), fatty acid recycling, and lipolysis, whereas in hypoxic conditions, SCFA + LPS decreased mRNA expression of genes involved in fat storage and triglyceride synthesis (p < 0.05), indicating different effects of SCFAs on adipocyte metabolic function depending on hypoxia status. Collectively, combined SCFAs in a 3:1:1 ratio beneficially modify the adipocyte adipokine secretory profile under both normoxic and hypoxic environmental conditions. Full article

Chronic inflammatory barrier diseases (CIBDs) affect many women of reproductive age, yet the safety of biologics during pregnancy remains inadequately investigated. This retrospective cohort study used the US Collaborative Network of TriNetX to evaluate the risk of adverse pregnancy outcomes (APOs) among women with CIBD receiving tumor necrosis factor inhibitors (TNFis), interleukin-23 inhibitors (IL-23is), or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), compared with untreated CIBD controls and the general pregnant population. Among 1842 pregnant women with CIBD receiving systemic therapy, 1188 were exposed to TNFis, 170 to IL-23is, 370 to azathioprine (csDMARD), and 114 to methotrexate (MTX) (csDMARD). The incidence of any APO ranged from 11% in untreated CIBD controls to 19% with ustekinumab (IL-12/23i). Among treatment groups, rates were 17% with TNFis, 18% with IL-23is, 13% with azathioprine, and 15% with MTX, compared with 17% in the general pregnant population. APO rates were comparable between the overall TNFi group and the TNFi group excluding certolizumab pegol (CZP) (TNFi). In the only non-exploratory comparison, TNFi exposure was associated with higher risks of (pre-)eclampsia and hypertension but a lower risk of abortion or intrauterine death versus CIBD controls, with no significant difference for overall APO. No treatment group showed a markedly increased overall APO risk, supporting tailored decision-making that balances the consequences of uncontrolled maternal disease against individual treatment-associated risks. Full article

Tear analysis plays a crucial role in the early screening and diagnosis of ophthalmic diseases. However, conventional methods are often limited by poor real-time performance, low portability, and insufficient capability for multi-parameter detection. Here, we present a bioinspired triboelectric electronic tongue integrated with a microfluidic chip for multimodal detection of tear pH and disease-related biomarkers. The system combines three triboelectric nanogenerator (TENG) modes, including droplet-based, dual-electrode sliding, and single-electrode sliding configurations. The droplet-based TENG converts gravitational potential energy into electrical energy, generating a maximum output voltage of 65 V. The sliding TENG further expands the sensing dimensions by characterizing droplet flow behavior and viscosity-related properties. Benefiting from the high sensitivity of the dual-electrode mode and the waveform differentiation capability of the single-electrode mode, the platform enables enhanced sample discrimination. After optimizing key parameters, including droplet height and chip inclination angle, the output stability errors for all three TENG modes were maintained within ±10%. Combined with a random forest algorithm, the multimodal sensing system achieved a classification accuracy exceeding 96.6% for artificial tears with different pH values. Moreover, distinct electrical response patterns were observed for ophthalmic disease-related biomarkers, including Lysozyme, Interleukin-6 (IL-6), and Chlamydia, demonstrating excellent type identification and concentration detection capability. This work provides a self-powered and miniaturized strategy for intelligent tear analysis and multiple-parameter sensing, offering significant potential for ophthalmic disease diagnosis. Full article

(1) Fibromyalgia syndrome (FMS) is a chronic pain disorder with a multifactorial pathogenesis involving neuroinflammation, oxidative stress, and immune dysfunction. This study aimed to evaluate serum biomarkers related to purinergic signaling, inflammasome activation, pyroptosis, and oxidative stress in patients with FMS. (2) Methods: A total of 93 patients with FMS and 93 age- and sex-matched healthy controls were enrolled. Serum levels of pannexin-1 (PANX1), purinergic receptor P2X7 (P2RX7), NLRP3, caspase-1 (CASP1), interleukin-1β (IL-1β), interleukin-18 (IL-18), gasdermin D (GSDMD), and gasdermin E (GSDME) were measured using enzyme-linked immunosorbent assays (ELISA). (3) Results: Total antioxidant status (TAS) and total oxidant status (TOS) were determined. Patients with FMS exhibited significantly increased serum CASP1, GSDME, PANX1, P2RX7, and total oxidative stress (TOS) levels, whereas GSDMD, NLRP3, IL-18, and TAS levels were significantly decreased compared with controls (all p < 0.05). No significant differences were observed in IL-1β levels. Receiver operating characteristic analysis demonstrated exploratory discriminatory performance within this case–control cohort for CASP1 and TAS (AUC = 0.898), followed by TOS (AUC = 0.849) and P2RX7 (AUC = 0.757). (4) Conclusions: These findings indicate alterations in circulating biomarkers related to purinergic signaling, inflammasome-associated pathways, pyroptosis-related proteins, and oxidative stress in patients with FMS. These alterations may contribute to the pathophysiology of FMS and provide a foundation for future mechanistic studies investigating their potential as biomarkers and therapeutic targets. Full article

Substance use disorders (SUDs) are increasingly associated with systemic inflammatory, neuroendocrine, and cardiometabolic dysregulation; however, the biological signatures underlying distinct substance-use patterns remain incompletely characterized. This study compared biomarker profiles among healthy controls and clinical groups comprising alcohol-associated polysubstance users (A + PS), non-alcohol substance users (PS-A), and alcohol-associated polysubstance users with comorbid post-traumatic stress disorder (PTSD+). Plasma levels of interleukin-6 (IL-6), C-reactive protein (CRP), cortisol, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were evaluated through comparative, multivariate, dose–response, and receiver operating characteristic (ROC) curve analyses. All clinical groups exhibited significantly increased IL-6, CRP, cortisol, and NT-proBNP levels compared with controls, indicating systemic physiological dysregulation associated with substance exposure. Among the evaluated biomarkers, IL-6 demonstrated the most robust and consistent performance across all analytical approaches. Multivariate regression identified alcohol consumption as an independent predictor of IL-6 elevation (p = 0.0003), while dose–response analysis revealed progressive increases in IL-6 according to alcohol consumption severity. ROC analysis further demonstrated that IL-6 exhibited the highest discriminatory performance (AUC = 0.844), outperforming CRP, cortisol, and NT-proBNP in distinguishing substance-using individuals from controls. Collectively, these findings were able to identify IL-6 as a central biomarker associated with substance-related systemic inflammatory dysregulation and support its translational potential as a sensitive indicator of physiological burden associated with chronic alcohol and substance exposure. Full article