Search Results (11,509)

Zoonotic bacterial pathogens are transmitted through various routes and are traditionally associated with acute febrile illnesses that may include pulmonary complications. However, in some survivors, the disease extends beyond the acute phase, leading to the remodeling of pulmonary architecture and driving progressive fibrosis. Although no direct cases have been reported, these pathogens may plausibly predispose injured lungs to carcinogenesis, similar to the well-recognized phenomenon of tuberculosis-associated scar cancer. As such long-term sequelae remain largely overlooked in current clinical practice, their potential contribution to fibrotic and malignant lung disease represents a critical and underexplored knowledge gap. This review proposes a unified mechanistic framework linking acute pathogen-mediated alveolar damage to chronic pulmonary fibrosis and subsequent lung carcinogenesis. We delineate four convergent biological pillars driving this continuum: (1) pathogen persistence establishing chronic Interleukin-1β (IL-1β)/Tumor necrosis factor-α (TNF-α)-mediated inflammation; (2) sustained TGF-β signaling and mechanotransduction driving progressive extracellular matrix remodeling; (3) unresolved reactive oxygen species (ROS) generation causing profound oxidative DNA damage; and (4) aberrant epithelial–mesenchymal transition (EMT) that perpetuates fibrosis and generates pre-malignant cell populations. Together, these sequelae alter lung biomechanics, suppress local immune surveillance, and create a mutagenic environment that is highly conductive to malignant transformation. Although direct epidemiological data remain emerging, the significant mechanistic overlap with idiopathic pulmonary fibrosis (IPF) presents a compelling rationale for shared oncogenic risk. We advocate for a paradigm shift in clinical practice, emphasizing the potential value of long-term surveillance for survivors of severe pulmonary infections. By integrating infectious diseases, pulmonology, and oncology, this framework highlights a neglected cause of fibrotic lung disease and establishes a foundation for future translational research. Full article

Background: Sertraline, a selective serotonin reuptake inhibitor widely prescribed for depressive disorders, has been proposed to exert immunomodulatory effects through modulation of inflammatory pathways; however, clinical evidence regarding its effects on circulating cytokines remains inconsistent. This systematic review and meta-analysis evaluated the effects of sertraline on inflammatory cytokines in adults. Methods: Searches were conducted in LILACS, CINAHL, MEDLINE/PubMed, Cochrane Library, Scopus, and Web of Science to identify randomized single- or double-blind placebo-controlled trials assessing sertraline and inflammatory biomarkers. Ten studies met the eligibility criteria. Random-effects meta-analyses were performed for interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α). Results: Sertraline did not significantly reduce circulating IL-6 (MD −1.06, 95% CI −2.32 to 0.19; I² = 86%; p = 0.10), IL-10 (MD < 0.01, 95% CI −0.23 to 0.23; I² = 72%; p = 0.98), or TNF-α levels (MD −0.84, 95% CI −4.04 to 2.37; I² = 72%; p = 0.61). Heterogeneity was substantial, all studies showed high overall risk of bias, and the certainty of evidence was very low for all outcomes. Conclusions: Current evidence does not support a significant or reliable anti-inflammatory effect of sertraline on circulating cytokines, and further well-designed trials using standardized inflammatory assessments are warranted. Full article

Glioblastoma remains the most lethal primary malignancy of the central nervous system, and the modest gains achieved with maximal surgery, radiotherapy and temozolomide have not been matched by the immune checkpoint inhibitors and antigen-specific vaccines that reshaped the treatment of many extracranial cancers. The recurrent disappointment of these approaches has been attributed less to a single molecular lesion than to a confluence of obstacles: profound intratumoural heterogeneity, a densely immunosuppressive and myeloid-rich microenvironment, sequestration and exhaustion of conventional T cells, and the practical difficulty of delivering effectors across the blood–brain barrier. Against this background, γδ T cells have attracted interest as an unconventional effector population that recognises transformed cells through stress-associated and metabolic cues rather than peptide–major histocompatibility complex (MHC) complexes, that kills in an MHC-unrestricted manner, and that can be expanded from healthy donors for allogeneic, off-the-shelf use with little expectation of graft-versus-host disease. This narrative review examines, with a deliberately critical lens, the biological rationale and the experimental evidence for γδ T cell-based immunotherapy of glioblastoma. We summarise the developmental biology and functional subsets of human γδ T cells, the natural killer group 2 member D (NKG2D)-, DNAX accessory molecule 1 (DNAM-1)- and T-cell-receptor-dependent mechanisms through which they engage glioblastoma cells and glioma stem-like cells, and the in vitro and animal-model studies that underpin the field, taking care not to overstate efficacy that has so far been demonstrated only in preclinical or early-phase settings. We then weigh the principal opportunities—locoregional and repeated dosing, combination with chemoradiotherapy, checkpoint blockade and antibody-based redirection—against barriers that include limited persistence, uncertain intratumoural trafficking, donor and manufacturing variability, and the unsettled requirements of potency testing and trial design. We give particular weight to what becomes of γδ T cells inside a hostile tumour—the exhaustion-like dysfunction that follows chronic stimulation, the oxygen and glucose dependence of their effector programme, the interleukin-17-polarising signals generated by activated microglia and by genotoxic therapy, and the confounding effect of corticosteroids—together with the engineering and pharmacological strategies proposed to counter them. The first peer-reviewed phase 1 report of intracranially delivered, drug-resistant γδ T cells has now appeared and documents tolerability in a small, single-arm cohort without establishing survival benefit. Throughout, γδ T cells are presented as a biologically plausible but still investigational strategy whose clinical value will be determined by adequately powered trials rather than by mechanistic appeal alone. Full article

Background/Objectives: Autoimmune hepatitis (AIH) is a liver injury characterized by the dysregulation of immune responses. Current options for AIH have limitations that highlight the urgent need to investigate alternative or adjunct therapeutic strategies for its management. We aimed to explore the protective effects of fasudil against concanavalin A (Con A)-induced AIH in mice. Con A resulted in significant hepatic damage, evidenced by dysregulation in liver function biomarkers, marked inflammatory cell infiltration, and hepatocellular degeneration. Methods: The pretreatment of mice with fasudil (10 and 25 mg/kg, intraperitoneally) for 7 days resulted in a significant ameliorative effect on these alterations in a dose-dependent manner. Fasudil treatment was associated with suppression of the RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) pathway and concomitant downregulation of toll-like receptor 4 (TLR4)/Nuclear factor-κB (NF-κB). Results: These changes were accompanied by reduced macrophage activation and the reduction of pro-inflammatory cytokines, as evidenced by decreased nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interferon gamma (INF-γ), and interleukin-17A (IL-17A). Moreover, it significantly limited the cluster of differentiation (CD)4⁺ and CD8⁺ T cell infiltration, thereby modulating adaptive immune amplification. Conclusions: Accordingly, fasudil restored redox homeostasis and mitigated hepatocellular death by rebalancing apoptotic regulators, normalizing the expression of B cell lymphoma 2 (BCL-2) while reducing the expression of BCL-2-associated X protein (BAX) and caspase-3 activation. Subsequently, fasudil improved liver function profiles and preserved hepatic architecture. Our results demonstrate that fasudil has potent immunomodulatory, anti-inflammatory, antioxidant, and anti-apoptotic effects in AIH. Its protective effects are associated with the suppression of RhoA/ROCK and TLR4/NF-κB signaling, supporting further investigation into the contribution of these pathways to the therapeutic actions of fasudil in AIH. Full article

Inflammatory bowel diseases (IBDs), chronic inflammatory disorders of the gastrointestinal tract, are classified into Crohn’s disease (CD) and ulcerative colitis (UC). Despite differing clinical manifestations, both CD and UC share a common immunopathogenesis, involving excessive production of proinflammatory cytokines by macrophages and dendritic cells. Tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and IL-23 are prototypical proinflammatory cytokines associated with CD and UC development, and biologics targeting these cytokines are widely used for treating patients with IBD. Antibodies (Abs) against IL-12 and IL-23 decrease intestinal inflammation by binding to the soluble forms of IL-12 and IL-23, respectively. Notably, anti-TNF-α Abs induce remission by neutralizing soluble TNF-α as well as membrane-bound TNF-α (mTNF-α). The binding of anti-TNF-α Abs to mTNF-α enables the diverse functions of IBD-specific TNF-α-inhibitors. Multiple modes of action of anti-TNF-α Abs for IBD include complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity, apoptosis of cells expressing mTNF-α, apoptosis of lamina propria T cells, and induction of regulatory T cells and macrophages. In this article, we introduce the diverse actions of anti-TNF-α Abs beyond TNF-α neutralization and discuss how these unique properties of anti-TNF-α Abs contribute to the efficient downregulation of IBD-associated inflammation. Full article

Background/Objectives: 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

Cancer progression is driven by early dysregulation of the immune system and tumor-intrinsic mechanisms. Hypoxia, lactate accumulation and IL-6 signaling induce highly overlapping tumor-promoting effects, including angiogenesis, epithelial–mesenchymal transition, metastasis, immune evasion and treatment resistance, suggesting that these pathways interact and amplify one another. This parallel activation complicates therapeutic targeting, as inhibition of one pathway may be compensated for by another. Increased proteolytic activity emerges early during tumor development and profoundly alters immune regulation. We recently identified a protease-generated albumin fragment, the IL-6-inducing factor (IL-6IF), which triggers pathological IL-6 production. IL-6 in turn enhances both HIF-1α expression and nuclear translocation, promotes glycolysis and lactate production, and forms positive feedback loops with STAT3 and multiple signaling pathways. Together, these mechanisms integrate into a self-sustaining IL-6/HIF-1α/STAT3 axis that drives tumor progression and suppresses anti-tumor immunity. The strong overlap among IL-6, its enhancing loops and hypoxia-driven mechanisms highlights IL-6 as a central regulator of metabolic and immunological reprogramming in cancer. However, a broad IL-6 blockade can impair physiological immune function. Selective inhibition of IL-6IF offers a novel strategy to prevent pathological IL-6 production while preserving physiological IL-6-dependent immune function required for effective tumor control. Reducing pathologically enhanced IL-6 synthesis by targeting IL-6IF, therefore, might represent a potential therapeutic approach to disrupt multiple tumor-promoting pathways simultaneously and may thereby improve responsiveness to cancer immunotherapy. Full article

This study evaluated dietary quercetin supplementation to investigate the effects of increasing inclusion levels on growth performance, diarrhea, serum health-related indicators, and whole-blood gene expression in weaned piglets. In a 28-day feeding trial, 128 piglets received diets formulated to contain 0, 100, 200, or 300 mg/kg quercetin (four pens of eight piglets per treatment; pen as the experimental unit). Final body weight and average daily gain were higher in the 200 and 300 mg/kg groups than in the control, and the 300 mg/kg group had the highest gain-to-feed ratio (G:F) (p < 0.05). Diarrhea rate declined linearly (p < 0.001); the rate in the 300 mg/kg group was lower than in the control and 100 mg/kg groups but did not differ from the 200 mg/kg group. Quercetin reduced serum malondialdehyde, pro-inflammatory cytokines, urea nitrogen, and aspartate aminotransferase, while increasing total protein, albumin, total antioxidant capacity, several antioxidant enzyme activities, and interleukin-10 (p < 0.05). Serum diamine oxidase activity and D-lactate concentration also declined linearly (p < 0.001). Whole-blood expression of PTGS2 decreased; HMOX1, NFE2L2, and NQO1 increased; and SOD1 was unchanged. Overall, within the tested range, increasing dietary quercetin improved growth and feed efficiency, reduced diarrhea, and was accompanied by coordinated changes in serum health-related indicators and whole-blood transcripts. Full article

Background/Objectives: Psoriasis is a chronic immune-mediated inflammatory disease primarily driven by the interleukin (IL)-23/T helper 17 (Th17) pathway. Despite multiple systemic therapies, treatment response varies considerably, and many patients require sequential switching. We aimed to evaluate circulating blood-derived biomarkers associated with response to systemic psoriasis therapies. Methods: MEDLINE and Web of Science were searched on 8 August 2025, following PRISMA guidance. The protocol was registered in PROSPERO (CRD420251129182). Eligible studies were original English- or Spanish-language studies published within the previous 10 years that evaluated circulating blood-derived biomarkers associated with cutaneous response to approved systemic psoriasis therapies in patients with psoriasis, with or without psoriatic arthritis. Genetic predictors, therapeutic drug monitoring studies, reviews, editorials, letters, conference abstracts, case reports, and non-original publications were excluded. Risk of bias was assessed using QUIPS and PROBAST. Quantitative synthesis included standardized mean difference meta-analysis and exploratory pooled p-value analysis. Results: Twenty-six studies were included. Most evaluated biologic therapies targeting TNF, IL-17, or IL-23; fewer assessed apremilast or methotrexate. Response definitions and follow-up varied across studies. Most studies showed moderate to high risk of bias, mainly due to small sample sizes, exploratory or post hoc analyses, heterogeneous treatment groups, limited confounding adjustment, multiple testing, and lack of external validation. Random-effects meta-analysis of baseline cytokines from two studies, including 71 patients per biomarker, showed no statistically significant differences between responders and non-responders for IL-17A, TNF-α, IL-6, IL-12, or IL-23. Exploratory pooled p-value analyses showed recurrent signals for downstream IL-23/Th17 biomarkers, particularly β-defensin-2 (BD-2; z = 4.63, p < 0.001), IL-17A (z = 3.27, p = 0.001), and IL-17F (z = 2.92, p = 0.003). Conclusions: Downstream IL-23/Th17 biomarkers, particularly BD-2 and IL-17 isoforms, showed recurrent exploratory associations with systemic treatment response. However, these findings should not be interpreted as evidence of superior predictive performance over upstream biomarkers, and no soluble circulating biomarker is currently ready for routine treatment selection. Full article

Ocular ischemic syndrome (OIS) is a vision-threatening disorder characterized by retinal ischemia, oxidative stress, and inflammation. In this study, the protective effects of anakinra, an interleukin-1 receptor antagonist, were investigated and compared with those of tocilizumab, an interleukin-6 receptor antagonist. Twenty-four male Wistar rats were randomly assigned to four groups (n = 6 per group): sham-operated (SG), carotid artery clamping/unclamping (CUG), anakinra-treated carotid artery clamping/unclamping (ACUG), and tocilizumab-treated carotid artery clamping/unclamping (TCUG). An experimental ocular ischemic injury model induced by transient bilateral common carotid artery occlusion was established by transient bilateral common carotid artery clamping followed by reperfusion. Retinal tissues were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) levels, and histopathological examinations were performed. OIS markedly increased MDA, TNF-α, IL-1β, and IL-6 levels while significantly decreasing tGSH, SOD, and CAT activities. Both anakinra and tocilizumab attenuated oxidative stress and inflammatory responses; however, anakinra produced notably greater improvements in MDA, tGSH, SOD, and CAT levels. Histopathological evaluation demonstrated that both treatments reduced retinal injury, edema, vascular congestion, and inflammatory cell infiltration. Although retinal architecture appeared slightly better preserved in the anakinra-treated group, histopathological scores were comparable between the treatment groups. These findings suggest that anakinra may attenuate oxidative and inflammatory retinal damage in this experimental ocular ischemic injury model and may provide greater biochemical protection than tocilizumab, whereas histopathological protection was comparable between treatments. Nevertheless, further experimental and clinical studies are required to confirm these findings. Full article

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease defined by persistent synovial inflammation, progressive cartilage and bone erosion, and extra-articular manifestations. Current treatments, such as disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, and non-steroidal anti-inflammatory drugs (NSAIDs), control disease activity but are limited by toxicity, reduced response over time, and are expensive, demonstrating the need for safer and more effective adjuncts. The marine environment is a rich, largely untapped source of structurally diverse bioactive molecules that could be used to develop new therapeutics. This review compiles current evidence on anti-inflammatory and immunomodulatory compounds from marine organisms relevant to RA, including macroalgae, true marine microalgae, marine microorganisms (bacteria and fungi, including deep-sea taxa), sea cucumbers, sponges, mussels, corals, and jellyfish. Recurring mechanisms of action include inhibition of the NF-κB, MAPK, and JAK/STAT signalling cascades; suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); reduced production of tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6; and activation of the Nrf2 antioxidant response. Particular attention is given to functional lipids (eicosapentaenoic and docosahexaenoic acids, prostaglandin-like oxylipins) and pigments (astaxanthin, fucoxanthin, β-carotene) from marine microalgae and heterotrophic protists, which recent literature identifies as the most clinically advanced marine leads. To clarify translational status, compounds are grouped by their development stage (marketed nutraceutical, clinical trial, or preclinical) and summarised in a dedicated table. Some compounds, such as green-lipped mussel extract, microalgal omega-3 oils, and astaxanthin, have reached the stage of randomised controlled trials for arthritis. However, most other potential treatments are still in the early, preclinical phase. It is worth noting that ocean-derived compounds appear generally safe, but more thorough studies, especially in living organisms and in clinical settings, are needed to confirm their effectiveness for rheumatoid arthritis before any claims can be made about their therapeutic benefits. Full article

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy in which antibodies against the aquaporin-4 (AQP4) water channel produce a stereotyped group of syndromes determined by the anatomical distribution of AQP4 expression. Six core clinical presentations are recognized: optic neuritis, longitudinally extensive transverse myelitis, area postrema syndrome, acute brainstem syndrome, diencephalic syndrome, and cerebral syndrome. Because disability in NMOSD almost always accrues at discrete, treatable relapses rather than through insidious progression, early recognition, supported by prompt AQP4-IgG testing and pattern recognition on MRI, is essential to preserving vision, mobility, and independence. This review summarizes the pathophysiology, clinical and radiologic features, diagnostic evaluation, and differential diagnosis of each core syndrome and synthesizes contemporary evidence for relapse prevention. Over the past decade, the therapeutic landscape has been transformed: agents targeting complement (eculizumab, ravulizumab), the interleukin-6 receptor (satralizumab, tocilizumab), and B cells (rituximab, inebilizumab) now have randomized evidence of efficacy in seropositive disease, with complement inhibitors ranking highest across indirect treatment comparisons. Evidence in seronegative disease remains limited, no approved agents have been compared head-to-head, and the optimal role of early plasma exchange is unsettled. Emerging neuroprotective strategies and chimeric antigen receptor T-cell therapy, both of which remain experimental, may further expand options for refractory disease. Once uniformly disabling, AQP4-IgG NMOSD is now a highly treatable condition in which timely diagnosis and sustained immunotherapy can meaningfully alter long-term outcomes. Full article

Acetyl L-carnitine is an ester of the trimethylated amino acid L-carnitine with well-documented neuroprotective properties. Despite its ability to cross the blood–brain barrier, acetyl L-carnitine requires high and repeated doses to achieve and maintain therapeutic concentrations in the central nervous system. To overcome these limitations, nanotechnology-based delivery systems have emerged as a promising strategy to improve drug bioavailability, targeting, and therapeutic efficacy. In this study, we evaluated the efficacy of nanoparticle-based formulations of acetyl L-carnitine in comparison with its conventional bulk form using in vitro cultures of SH-SY5Y neuroblastoma cell line. The ALC nanoparticles were produced through an organic solvent-free mechanical ball milling process employing a planetary ball mill. The dimension and stability of the nanoparticles were analyzed by Dynamic Light Scattering and Thermogravimetric Analysis. The biological effects were evaluated using quantitative Real Time-Polymerase Chain Reaction, Enzyme-linked Immunosorbent Assay and immunofluorescence experiments. ALC nanoparticles, at low concentration of nanoparticles compared to the non-nanoparticle form, were able to decrease the alarmin S100B release, pro-inflammatory interleukin mRNA and protein expression as well as p65 activation, confirming their involvement in NF-κB pathway. Moreover, it was able to stimulate the nerve growth factor release and to increase intracellular Ca⁺⁺ levels, showing neuroprotective effects in addition to anti-inflammatory ones. Our findings allow us to highlight the therapeutic potential of ALC nanoparticles for neurological disorders, with the prospect of enhancing efficacy while reducing dosage and administration frequency. Full article

Background: Obesity and periodontitis share inflammatory pathways. This pilot randomized controlled trial evaluated salivary IL-6 and TNF-α and periodontal changes after sleeve gastrectomy (SG) versus non-surgical management (NSG). Methods: Thirty-two adults with obesity and stage I–III periodontitis were randomized to SG (n = 18) or NSG (n = 14) and assessed at baseline, 3 months, and 6 months. Primary outcomes were salivary IL-6 and TNF-α; secondary outcomes were PI, BOP, PPD, and CAL. Results: At 6 months, SG participants had lower BMI than NSG participants (32.20 ± 3.90 vs. 42.10 ± 4.30 kg/m²; p = 0.0001). Primary cytokine outcomes also favored SG: IL-6 was 3.72 ± 1.08 vs. 6.34 ± 1.37 pg/mL and TNF-α was 5.11 ± 1.29 vs. 7.71 ± 1.68 pg/mL (both p = 0.0001). PI and BOP were lower in SG than NSG (38.60 ± 9.80% vs. 60.80 ± 10.40% and 20.80 ± 7.40% vs. 39.70 ± 9.10%; both p = 0.0001), while PPD was modestly lower (2.89 ± 0.43 vs. 3.31 ± 0.46 mm; p = 0.017) and CAL was not significantly different (p = 0.15). Conclusions: These preliminary pilot findings suggest parallel reductions in salivary inflammatory markers and plaque-related/gingival-inflammatory indices after SG, but behavioral confounding, complete-case analysis, short follow-up, and absent significant CAL gain preclude causal or regenerative conclusions. Full article

Background: Chronic low back pain (CLBP) is a leading cause of global disability, linked to elevated IL-6 and vitamin D deficiency or insufficiency. While interferential current (IFC) therapy and exercise therapy are established treatments, their combined effect with vitamin D supplementation on inflammatory biomarkers, pain, and functional disability remains underexplored. Objective: The aim of this study was to evaluate the combined effects of physiotherapy and vitamin D supplementation on pain, disability, IL-6 expression, and vitamin D levels in CLBP patients. Methods: This two-arm, parallel-group, randomized controlled trial enrolled 60 CLBP patients, randomized into Group A (physiotherapy alone: IFC therapy and exercise therapy; n = 30) or Group B (physiotherapy plus vitamin D supplementation; n = 30). Outcomes included pain intensity (11-point Numeric Pain Rating Scale (NPRS)), disability (Arabic Oswestry Disability Index (ODI), 0–100%), and serum IL-6 and 25-hydroxyvitamin D (both by ELISA; pg/mL and ng/mL, respectively), which were assessed at baseline and 6 weeks. All 60 participants enrolled had laboratory-confirmed vitamin D deficiency or insufficiency (serum 25(OH)D < 20 ng/mL) at screening. Independent samples t-tests compared continuous baseline characteristics and between-group differences in 6-week change scores; paired t-tests assessed within-group change from baseline to 6 weeks; the chi-square test compared the categorical variable of gender (α = 0.05). Results: Both groups showed significant improvements in NPRS and ODI at six weeks (p < 0.001). Group B demonstrated significant reductions in NPRS (−3.01 vs. −1.71) and ODI (21.83% vs. 16.33%). IL-6 decreased significantly only in Group B (18.24 pg/mL, p < 0.001), with no significant change in Group A (25.96 pg/mL, p = 0.626). Vitamin D levels increased significantly in Group B (31.68 ng/mL, p < 0.001) compared with Group A (19.68 ng/mL, p = 0.115), a between-group difference that was also statistically significant. Conclusions: Combining physiotherapy with vitamin D supplementation improves outcomes in the management of CLBP. This approach effectively reduces pain, functional disability, inflammation, and vitamin D deficiency or insufficiency, offering a comprehensive, evidence-based treatment strategy. Full article