Inflammation Research[JOURNAL]
Sun
200 papers
Cav-1 deficiency induces cardiac dysfunction via the AdipoR1-AMPK-mTOR autophagy pathway.
An Z, Liu L, Zhao X … +6 more , Zhang L, Yang X, Zhang H, Ge C, Tian J, Song X
Inflamm Res · 2026 Jan · PMID 41591548 · Publisher ↗
OBJECTIVE AND DESIGN: This study aimed to investigate the mechanism by which Caveolin-1 (Cav-1) deficiency leads to cardiac dysfunction, utilizing both in vivo and in vitro experimental models. MATERIAL OR SUBJECTS: Expe...
OBJECTIVE AND DESIGN: This study aimed to investigate the mechanism by which Caveolin-1 (Cav-1) deficiency leads to cardiac dysfunction, utilizing both in vivo and in vitro experimental models. MATERIAL OR SUBJECTS: Experiments used 43-52-week-old wild-type (WT) and Cav-1 knockout (Cav-1) mice (n=5 per group), and the H9C2 rat cardiomyocyte cell line. TREATMENT: In vivo, Cav-1mice received rapamycin (0.25 mg/kg). In vitro, H9C2 cells underwent Cav-1 knockdown/overexpression and were treated with rapamycin (100 nM), chloroquine (20 µM), AMPK activator A-769662, adiponectin (APN, 5 µg/ml), or AdipoR1 overexpression. METHODS: Cardiac function was assessed by echocardiography (LVEF, LVFS). Protein expression was analyzed via western blotting and immunofluorescence. Autophagic flux was measured using mRFP-GFP-LC3B lentivirus. Apoptosis was evaluated by TUNEL staining and flow cytometry. Data are mean ± SD; statistical analysis used t-tests/ANOVA. RESULTS: Cav-1 mice exhibited impaired cardiac function (LVEF: reduced vs. WT, p<0.05), suppressed autophagy, increased apoptosis, and elevated inflammation/fibrosis. In H9C2 cells, Cav-1 knockdown inhibited AMPK phosphorylation, activated mTOR, and repressed autophagy, effects reversed by Cav-1 overexpression or rapamycin/AMPK activation. Bioinformatic and immunofluorescence analyses identified AdipoR1 downregulation in Cav-1 hearts; APN/AdipoR1 overexpression rescued autophagy and reduced apoptosis. CONCLUSIONS: Cav-1 deficiency induces cardiac dysfunction by suppressing autophagy via the AdipoR1-AMPK-mTOR pathway, highlighting Cav-1 as a potential therapeutic target for cardiac dysfunction.
Differential clinical factors influencing the effectiveness of distinct biologic agents in psoriasis: insights from a prospective cohort study in China.
Dai M, Jiang Y, Wang Y … +6 more , Huang D, Wang Y, Hu Y, Gao Y, Yu Q, Shi Y
Inflamm Res · 2026 Jan · PMID 41591532 · Publisher ↗
OBJECTIVE AND DESIGN: This prospective multicenter cohort study was conducted to identify and compare clinical factors associated with the effectiveness of commonly used biologics in Chinese patients with moderate-to-sev...
OBJECTIVE AND DESIGN: This prospective multicenter cohort study was conducted to identify and compare clinical factors associated with the effectiveness of commonly used biologics in Chinese patients with moderate-to-severe psoriasis. SUBJECTS: Patients from the SPEECH registry initiating treatment with ixekizumab, secukinumab, guselkumab, or ustekinumab were included. TREATMENT: Guideline-recommended dosing; 3-month follow-up. METHODS: The primary endpoint was PASI90 response at 3 months. Multivariable logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for clinical predictors of treatment response. RESULTS: A total of 717 patients were included in the analysis. In guselkumab-treated patients, obesity (aOR 0.22, 95% CI 0.06-0.78) and prior biologic exposure (aOR 0.22, 95% CI 0.06-0.75) were independently associated with reduced PASI90 response. Psoriatic arthritis predicted poorer response to ustekinumab (aOR 0.16, 95% CI 0.03-0.78). For secukinumab, male sex reduced the likelihood of PASI90 (aOR 0.47, 95% CI 0.23-0.96), whereas family history of psoriasis improved outcomes (aOR 2.20, 95% CI 1.10-4.42). In ixekizumab-treated patients, obesity (aOR 0.38, 95% CI 0.18-0.80) was a negative predictor, while family history (aOR 2.79, 95% CI 1.22-6.38) enhanced treatment response. CONCLUSIONS: Predictors of biologic effectiveness differ by agent, supporting personalized treatment based on patient characteristics.
Intestinal epithelial AhR deletion aggravates DSS-induced colitis via lipid- and amino-acid metabolic reprogramming: integrated metabolomic-transcriptomic evidence.
Zhang Y, Liu F, Xu C … +6 more , Wang L, Yang Y, Xiong M, Zhao B, Yu M, Yang H
Inflamm Res · 2026 Jan · PMID 41591506 · Publisher ↗
BACKGROUND: Recent studies reveal that the interaction of Aryl Hydrocarbon Receptor (AhR) signaling activation with metabolic homeostasis may significantly affect the course of IBD, and the inhibition of AhR signaling ma...
BACKGROUND: Recent studies reveal that the interaction of Aryl Hydrocarbon Receptor (AhR) signaling activation with metabolic homeostasis may significantly affect the course of IBD, and the inhibition of AhR signaling may exacerbate IBD symptoms and disrupt epithelial barrier function. However, there is no recognition of how the AhR signaling pathway affects intestinal barrier function by influencing intestinal epithelial cell metabolism. METHODS: In this study, we constructed intestinal epithelial-specific AhR knockout mice, and performed comprehensive metabolomic and transcriptomic analyses on four groups of mice (WT mice, DSS mice, AhR mice, and AhR+DSS mice) in order to assess the metabolic and genomic effects of AhR signaling deletion in intestinal epithelial cells. RESULTS: Compared with wild-type mice, the knockout of the AhR gene caused characteristic changes mainly in lipid metabolism and amino acid metabolism disorders, including 69 metabolites and 64 genes. Under inflammatory conditions, changes including 94 metabolites and 3062 genes were observed in the DSS group compared to wild-type mice.In addition, down-regulation of 14 metabolites and up-regulation of 11 metabolites were observed in AhR+DSS mice compared to DSS, with anti-inflammatory metabolites such as 13-hydroxy-4Z,7Z,10Z,14E,16Z,19Z-docosahexaenoic acid、prostaglandin i2, pg 42: 11, 1,2-distearoyl-sn-glycero-3-phospho-l-serine decreased dramatically, whereas the pro-inflammatory metabolites prosapogenin a, 12,13-dihydroxy-9z-octadecenoic acid, pro-leu, n-acetyl-l-aspartic acid increased significantly. Analysis of RNA-Seq data showed that the genetic changes caused by AhR knockdown were mainly focused on lipid metabolism, amino acid metabolism and other pathways. In addition, comprehensive metabolomic and transcriptomic analyses showed that in the correlation analysis of 25 metabolites and 30 differentially expressed genes, pro-inflammatory factor Saa1 was positively correlated with multiple pro-inflammatory metabolites such as pro-leu and pheniramine, while the anti-inflammatory factor Saa3 was positively associated with several anti-inflammatory metabolites such as prostaglandin i2, 1,2-distearoyl-sn-glycero-3-phospho-l-serine. CONCLUSION: These genes and metabolites involved in metabolic dysregulation pathways may provide a more specific and reliable research direction to study the protective mechanisms of AhR on the intestinal epithelial barrier and provide new insights into the effects of AhR on regulating the metabolism of intestinal epithelial cells in the development of IBD.
Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle.
Toriola MA, Timlin E, Bulbule S … +6 more , Reyes A, Adedeji OM, Gottschalk CG, Barua A, Arnold LA, Roy A
Inflamm Res · 2026 Jan · PMID 41591477 · Full text
OBJECTIVE: M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear. RESULTS: Our study showed that hemizygous deletion of the early autophagy gene atg13 (Tg+/-ATG13) d...
OBJECTIVE: M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear. RESULTS: Our study showed that hemizygous deletion of the early autophagy gene atg13 (Tg+/-ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, and increases reactive oxygen species (ROS) levels in splenic macrophages, leading to M1 polarization. After reducing the expression of the autophagy markers WDFY3 and LC3, flow cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), decreasing oxygen metabolism, as evaluated by the ROS-sensor dye DCFDA, and Seahorse oxygen consumption studies revealed that ablation of the atg13 gene impairs mitochondrial function, triggering M1 polarization. Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages and contributing to the inflammatory response in M1Mφs. Additionally, ablation of the atg13 gene resulted in increased infiltration of M1Mφs into the muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise. CONCLUSIONS: Our study shows that impaired ATG13-driven autophagy increases inflammation through sirtuin-1 inactivation and NF-κB activation, suggesting a role for ATG13 in post-exertional malaise (PEM).
Inhibiting METTL3 in macrophages alleviates colitis by enhancing M2 polarization via upregulating IRAKM.
Zhang Y, Wang X, Cao S … +2 more , Liu Y, Xu J
Inflamm Res · 2026 Jan · PMID 41591461 · Publisher ↗
OBJECTIVE AND DESIGN: N6-methyladenosine (mA), the most prevalent RNA modification, plays a crucial role in regulating macrophage homeostasis and intestinal immunity, although its mechanism remains largely unknown. A lin...
OBJECTIVE AND DESIGN: N6-methyladenosine (mA), the most prevalent RNA modification, plays a crucial role in regulating macrophage homeostasis and intestinal immunity, although its mechanism remains largely unknown. A link between increased methyltransferase-like 3 (METTL3) expression in macrophages and intestinal inflammation has been confirmed. Herein, we sought to determine the role of METTL3-mediated macrophage activation in colitis. METHODS: The dextran sulfate sodium (DSS)-induced experimental colitis model was established. Conditional knockout of METTL3 in myeloid cells mice (Mettl3Lyz2) and myeloid cells-specific deletion of IRAKM mice (IrakmLyz2) were generated, respectively. The severity of colitis was measured using the disease activity index, colon length, and histopathological staining. Various techniques such as flow cytometry, western blot, quantitative PCR, and RNA-seq analysis were employed to assess polarization and the expression of inflammatory cytokines. RESULTS: Conditional knockout of Mettl3 in myeloid cells attenuated intestinal inflammation in experimental colitis. In vivo and in vitro studies confirmed that Mettl3 deletion skewed macrophages towards M2 activation. Mechanistically, Irakm, a negative regulator of TLR4 signaling, was identified as a target of METTL3-mediated mA modification. METTL3 deficiency led to a higher level of IRAKM, which ultimately suppressed TLR signaling-mediated macrophage activation. Myeloid cells-specific deletion of Irakm mice were more susceptible to DSS-induced colitis than were wild-type mice. Colon-infiltrating M1 macrophages from IrakmLyz2 mice dramatically increased compared with those from their counterpart Irakm mice. Additionally, deletion of IRAKM in bone marrow-derived macrophages (BMDMs) induced NF-κB activation and facilitated M1 polarization. CONCLUSION: Our study highlights the role of METTL3-IRAKM signaling in macrophage polarization and intestinal inflammation, providing a potential therapeutic target for the treatment of colitis.
Nanozyme-based therapies for inflammatory immune disorders: opportunities and challenges.
Zhang W, Cai S, Ma J … +2 more , Gao R, Dong L
Inflamm Res · 2026 Jan · PMID 41591456 · Publisher ↗
BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are chronic disorders involving multiple organs and driven by shared pathogenic pathways. Current therapeutic approaches, such as disease-modifying anti-rheumatic...
BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are chronic disorders involving multiple organs and driven by shared pathogenic pathways. Current therapeutic approaches, such as disease-modifying anti-rheumatic drugs (DMARDs) and biologics, are limited by infection risks, poor tissue specificity, and suboptimal long-term efficacy, underscoring the need for novel therapies. Nanozymes, nanomaterials with enzymatic activities, have garnered considerable interest for treating IMIDs due to their potential to counteract oxidative stress. Nevertheless, a systematic assessment of their therapeutic applications, mechanisms, and clinical translation challenges in IMIDs remains lacking. FINDINGS: Given the critical pathogenic role of reactive oxygen species (ROS) in IMIDs, nanozymes, particularly those with oxidoreductase activity, have demonstrated significant therapeutic potential. They modulate ROS levels, restore immune homeostasis, and remodel the local inflammatory microenvironment, either as monotherapy or in combination with conventional agents. To overcome challenges such as biosafety, off-target effects, and clinical translatability, strategies successfully explored in other diseases, such as biodegradable or organic-inorganic hybrid nanozymes, pH-responsive targeting designs, erythrocyte membrane coatings, and ROS-responsive carriers, may be adapted to enhance tissue specificity and safety in IMID treatment. Further investigation is warranted to adapt and optimize these strategies for effective and safe nanozyme-based therapy in IMIDs. CONCLUSION: This review synthesizes current evidence to summarize the therapeutic potential and underlying mechanisms of nanozymes in IMIDs, while highlighting key challenges and future directions to guide the development and clinical translation of nanozyme-based therapies.
S100A8 aggravates sepsis-associated encephalopathy by promoting PFKFB3-dependent glycolysis and microglial neuroinflammation.
Hu H, Peng S, Chen J … +6 more , Li D, Wu S, Jiang H, Lu Y, Song Y, Zhu W
Inflamm Res · 2026 Jan · PMID 41591450 · Publisher ↗
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common and severe neurological complication of sepsis that markedly worsens long-term outcomes. Growing evidence suggest that metabolic reprogramming in microglia i...
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common and severe neurological complication of sepsis that markedly worsens long-term outcomes. Growing evidence suggest that metabolic reprogramming in microglia is a major driver of neuroinflammation in SAE; however, the molecular mechanisms that altered metabolism and inflammatory responses remain unclear. METHODS: Transcriptomic data from public hippocampal datasets of SAE mice were analyzed to identify potential molecular drivers. We established a CLP-induced SAE model and performed AAV-mediated knockdown. For in vitro validation, BV2 microglia were treated with LPS to simulate neuroinflammation. Mechanistic validation was conducted using both genetic and pharmacological interventions. Cellular metabolism was examined through extracellular flux analysis and metabolite detection. Inflammatory responses were evaluated by cytokine profiling, and disease phenotypes were assessed using behavioral tests and histological analyses. RESULTS: S100A8 was markedly upregulated in activated microglia during SAE. Its knockdown reduced microglial activation, protected hippocampal neurons, and improved cognitive performance. Transcriptomic profiling identified PFKFB3 as a downstream glycolytic target of S100A8. Mechanistically, S100A8 activated the PI3K/AKT/HIF-1α signaling cascade, thereby upregulating PFKFB3 and promoting glycolytic reprogramming and cytokine release. Functionally, S100A8 knockdown lowered lactate production and LDH activity, while reducing TNF-α, IL-6, and IL-1β secretion. Rescue experiments confirmed that PFKFB3 mediates the glycolytic and pro-inflammatory effects of S100A8. CONCLUSIONS: This study demonstrates that S100A8 exacerbates SAE-related neuroinflammation and cognitive impairment by driving microglial metabolic reprogramming toward glycolysis via the PI3K/AKT/HIF-1α-PFKFB3 pathway. These findings highlight a mechanistic link between S100A8 and microglial metabolic reprogramming and neuroinflammation, and suggest that S100A8 could be a promising target for therapeutic intervention in SAE.
Recombinant TsP53 mitigates inflammation and blood-brain barrier disruption in CLP-induced septic mice.
Zhezhi D, Zaiyuan S, Gengxin L … +5 more , Wenqian G, Jifeng G, Li G, Lingyu W, Jia X
Inflamm Res · 2026 Jan · PMID 41591410 · Publisher ↗
BACKGROUND: Sepsis-associated encephalopathy (SAE), a neurological complication of sepsis without direct CNS infection, currently lacks established pharmacological therapy. Key pathological features include excessive mic...
BACKGROUND: Sepsis-associated encephalopathy (SAE), a neurological complication of sepsis without direct CNS infection, currently lacks established pharmacological therapy. Key pathological features include excessive microglial activation and blood-brain barrier (BBB) disruption. Our prior work showed that recombinant Trichinella spiralis 53-kDa glycoprotein (rTsP53) modulates intestinal endothelial tight junctions in septic mice by downregulating inflammation. METHODS: We analyzed inflammatory factor levels and performed bioinformatics analysis on cerebrospinal fluid (CSF) from SAE patients. In a cecal ligation and puncture (CLP)-induced septic mouse model, we assessed brain inflammatory cytokines, BBB permeability, tight junction protein expression, microglial activation, and transcription factor p65 levels. Mice were prophylactically treated with rTsP53 prior to septic insult. RESULTS: CSF from SAE patients showed significantly elevated inflammatory factors and upregulated leukocyte migration/chemotaxis pathways. CLP-induced septic mice exhibited increased brain inflammatory cytokines, enhanced BBB permeability, reduced tight junction protein expression, microglial activation, and elevated p65. Prophylactic rTsP53 treatment decreased pro-inflammatory cytokines (IL-6, IL-17A) and p65, increased anti-inflammatory factors (IL-4, IL-13), and alleviated BBB damage. CONCLUSION: Prophylactic rTsP53 mitigates sepsis-induced brain inflammation and BBB disruption in mice by modulating the microglial response. These findings provide preclinical evidence supporting the further exploration of rTsP53 as a potential preventive agent for SAE.
Longitudinal biomarker trajectories and their prognostic utility for 21-day mortality in burn patients with sepsis: a retrospective cohort study.
Lou J, Kong H, Li J … +8 more , Xiang Z, Zhu X, Cui S, Huang N, Xu S, Jin G, Le X, Fan Y
Inflamm Res · 2026 Jan · PMID 41563442 · Full text
OBJECTIVE: To characterize the longitudinal trajectories of multi-category biomarkers and evaluate their association with 21-day all-cause mortality in critically ill burn patients with sepsis. METHODS: In this retrospec...
OBJECTIVE: To characterize the longitudinal trajectories of multi-category biomarkers and evaluate their association with 21-day all-cause mortality in critically ill burn patients with sepsis. METHODS: In this retrospective single-center cohort study, we analyzed 943 adult burn patients with sepsis, defined per Sepsis-3.0 criteria. Serial measurements of 15 biomarkers across nutritional, immunoglobulin, lymphocyte subset, inflammatory, and other categories were collected over 21 days. We employed linear mixed-effects models (LME) to compare trajectories between survivors and non-survivors, Cox regression to assess associations with mortality, time-dependent ROC to evaluate predictive performance, and k-means clustering to identify patient phenotypes based on integrated ALB, IL-6, and IgG trajectories. RESULTS: The 21-day mortality was 17.92%. LME revealed significantly different trajectories for 11 biomarkers between survivors and non-survivors (P < 0.05). Univariate Cox analysis identified multiple significant biomarkers, with transferrin (HR = 0.985, P = 6.84 × 10⁻) and IgM (HR = 0.284, P = 1.24 × 10⁻) as strong protective factors, and mitochondrial DNA (HR = 1.002, P = 1.89 × 10⁻⁹) as a risk factor. In multivariate analysis, only the Burn Index remained an independent risk factor (HR = 1.066, P < 0.001). Time-dependent ROC showed peak predictive accuracy at Day 7 (albumin AUC = 0.729). Clustering identified three distinct phenotypes-"Rapid Recovery" (mortality 5.2%), "Persistent Inflammatory & Catabolic" (mortality 38.0%), and "Intermediate" (mortality 18.7%; P < 0.001)-with starkly different biomarker trends and clinical profiles. CONCLUSIONS: The dynamic patterns of multi-category biomarkers are strongly associated with short-term survival in burn sepsis. While burn severity is a dominant baseline risk factor, longitudinal trajectory analysis captures the essence of the host's recovery or failure, effectively stratifying patients into prognostically distinct subgroups. This trajectory-based phenotyping highlights the potential of monitoring the host response over time to improve risk assessment and guide personalized management.
Erianin protects chondrocytes against IL-1β-induced oxidative stress and ferroptosis by activating GPX4/STING signaling in osteoarthritis.
Li C, Jian W, Lu S … +2 more , Wang Y, Fang C
Inflamm Res · 2026 Jan · PMID 41533098 · Full text
BACKGROUND: Erianin (Eri) has been known for its analgesic and antipyretic properties. This research focuses on impact of Eri on chondrocyte viability, inflammatory cytokine production, extracellular matrix (ECM) degrada...
BACKGROUND: Erianin (Eri) has been known for its analgesic and antipyretic properties. This research focuses on impact of Eri on chondrocyte viability, inflammatory cytokine production, extracellular matrix (ECM) degradation, and ferroptosis, which are key factors in cartilage diseases. METHODS: The mouse model of osteoarthritis (OA) was induced by destabilization of medial meniscus (DMM). Chondrocytes were treated with different concentrations of Eri and exposed to IL-1β to simulate disease conditions. The chondrocytes were induced to undergo ferroptosis using erastin (Era), and ferroptosis was inhibited by Fer-1. This was done to form an intervention control group in combination with Era and to explore the synergistic effect. The effects of Eri on cell viability, proliferation, inflammatory responses, ECM degradation, and ferroptosis were assessed using CCK-8 analysis, EDU assay, Western blot, immunofluorescence, ROS staining, and flow cytometry. The Cellular Thermal Shift Assay (CETSA) was also employed to confirm the direct binding and thermal stability of GPX4 and STING in the presence of Eri. RESULTS: The findings indicate that Eri does not exhibit cytotoxic effects at certain concentrations and can actually enhance chondrocyte proliferation and viability. It also reduces the production of inflammatory cytokines and ECM degradation products, suggesting a protective role against cartilage damage. Furthermore, Eri was found to inhibit ferroptosis in chondrocytes, potentially through the activation of the GPX4/STING signaling pathway. Molecular docking combined with CETSA confirmed that Eri enhances the thermal stability of GPX4 and STING, indicating a stabilizing effect on this key enzyme. In the DMM mouse model, Eri significantly alleviated cartilage degeneration and improved chondrocyte function, as evidenced by reduced osteophyte formation and subchondral bone sclerosis. Eri can act independently or in combination with the ferroptosis inducer erastin (Era) and the ferroptosis inhibitor Ferrostatin-1 (Fer-1). By inhibiting lipid peroxidation, regulating cell proliferation and extracellular matrix degradation, it exerts an intervention effect on IL-1β-induced ferroptosis of chondrocytes. Moreover, when used in combination with Fer-1, it has a synergistic enhancing effect in reversing ferroptosis-related damage. CONCLUSIONS: Eri demonstrates promising therapeutic potential in the treatment of OA by inhibiting chondrocyte ferroptosis and protecting against ECM degradation and inflammatory responses.
Machine learning and multi-omics integration identifies immunological predictors and mechanistic insights in autoimmune encephalitis.
Guo J, Zou Y
Inflamm Res · 2026 Jan · PMID 41533076 · Publisher ↗
OBJECTIVE: To develop an interpretable prognostic prediction model for autoimmune encephalitis (AE) using immunological indicators and to investigate the potential role of nucleophosmin (NPM1) in disease pathogenesis thr...
OBJECTIVE: To develop an interpretable prognostic prediction model for autoimmune encephalitis (AE) using immunological indicators and to investigate the potential role of nucleophosmin (NPM1) in disease pathogenesis through multi-omics approaches. METHODS: We enrolled patients diagnosed with antibody-positive AE and analyzed a broad panel of immunological indicators. Prognostic prediction models were developed using eight machine learning algorithms and validated in an independent cohort. Model interpretability was enhanced through SHapley Additive exPlanations (SHAP) analysis. We further evaluated the therapeutic potential of protein A immunoadsorption (PAIA) in reducing pathogenic antibodies. Building upon these clinical and immunological findings, we sought to investigate the underlying mechanisms by exploring the role of nucleophosmin (NPM1). To this end, we integrated single-cell RNA sequencing and spatial transcriptomics in an experimental autoimmune encephalomyelitis (EAE) model and conducted a phenome-wide association study (PheWAS) to assess its safety as a potential therapeutic target candidate. RESULTS: Six key immunological indicators were identified for model construction: cerebrospinal fluid /serum IgG quotient (QIgG), lymphocyte count, double negative T cell count, double positive T cell count, NK cell count, and T cell percentage. The RF, XGBoost, and LGBM models demonstrated high predictive performance, with AUC values of 0.978, 0.917, and 0.900, and accuracies of 0.940, 0.916, and 0.831, respectively. Anti-NMDAR antibody titers in cerebrospinal fluid decreased (from 1:3.2 to 1:1) following PAIA treatment in a single patient. Cell communication analysis revealed enhanced intercellular signaling in the high-Npm1 expression group, particularly involving the PSAP pathway. Spatial transcriptomics confirmed upregulated Npm1 expression in EAE lesions. PheWAS indicated no significant off-target effects associated with NPM1. CONCLUSION: This study provides an interpretable prognostic framework for AE, presents preliminary evidence for PAIA, and nominates NPM1 as a potential mechanistic player in disease pathogenesis. Its suitability as a potential therapeutic target requires further safety validation, despite the absence of significant signals in the preliminary PheWAS.
Comparison of cancer risks associated with JAK inhibitors and TNF inhibitors treatment in patients with rheumatoid arthritis: a systematic review and meta-analysis of real-world cohort studies.
Yang FY, Liu YC, Wu MY … +2 more , Wu YC, Hung CH
Inflamm Res · 2026 Jan · PMID 41504972 · Publisher ↗
INTRODUCTION: Potential increased cancer risk associated with janus kinase inhibitors (JAKi) compared with anti-tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) remains a concern. Publis...
INTRODUCTION: Potential increased cancer risk associated with janus kinase inhibitors (JAKi) compared with anti-tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) remains a concern. Published cohort studies have reported conflicting results, and the discrepancies between randomized trials and real-world data remain unclear. We conducted this systematic review and meta-analysis to assess this association. MATERIAL/METHODS: We systematically searched PubMed, Embase and Cochrane Library for cohort studies up to January 31, 2025, comparing JAKi with TNFi and reporting cancer outcomes in RA patients. The primary outcome was overall cancer risk, and secondary outcomes included site-specific cancers. Pooled hazard ratios (HR) with 95% confidence intervals (CI) were calculated using a random-effects meta-analysis. Subgroup and sensitivity analyses were conducted to explore potential sources of heterogeneity. The certainty of evidence (CoE) were assessed using the GRADE framework. RESULTS: We included 5 cohort studies with 137,640 RA patients. Compared to TNFi, JAKi did not increase the risk of overall cancers (pooled HR: 1.06, 95% CI: 0.81-1.37; CoE: very low). Regarding secondary outcomes, JAKi was not linked to most cancers but increased the risk of non-melanoma skin cancer (NMSC) (HR: 1.21, 95% CI: 1.03-1.41; CoE: very low). The finding was consistent across multiple subgroup and sensitivity analyses. CONCLUSION: This meta-analysis found no increase in overall cancer risk with JAKi compared to TNFi, but identified an increased risk of NMSC, suggesting the need for regular dermatologic surveillance.
Targeting neuroinflammation in neurodegenerative disorders: the emerging potential of semaglutide.
Evola V, Parmar MS
Inflamm Res · 2026 Jan · PMID 41504939 · Publisher ↗
BACKGROUND: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's dis...
BACKGROUND: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses. FINDINGS: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation. CONCLUSION: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.
Knockdown of caspase-activated DNase and B-cell lymphoma 2 inhibits cell proliferation and drug resistance in TP53-mutant multiple myeloma.
Tian F, Wang J, Zhang P … +7 more , Jiang J, Cheng X, Li J, Tang M, Fan J, Yan P, Zhao G
Inflamm Res · 2026 Jan · PMID 41504908 · Publisher ↗
OBJECTIVE: TP53 mutations are infrequently found in multiple myeloma (MM), a malignancy characterized by the clonal proliferation of plasma cells that secrete monoclonal immunoglobulin. This study explored the mechanism...
OBJECTIVE: TP53 mutations are infrequently found in multiple myeloma (MM), a malignancy characterized by the clonal proliferation of plasma cells that secrete monoclonal immunoglobulin. This study explored the mechanism of caspase-activated DNase (CAD) and B-cell lymphoma 2 (BCL-2) in regulating proliferation and drug resistance of TP53-mutant MM cells. METHODS: TP53 wild-type (H929) and TP53-mutant (U266 and RPMI-8226) MM cell lines were cultured under standard conditions. TP53-mutant cells were transfected with lentiviral shRNA plasmids targeting CAD and BCL-2 (Lv-sh-CAD and Lv-sh-BCL-2). Cell viability, proliferation, apoptosis, and cell cycle, as well as the levels of CAD, BCL-2, cell cycle-related proteins (P21, Cyclin D1, Cyclin-dependent kinase 1 [CDK1]) and drug resistance-associated proteins (adenosine triphosphate-binding cassette subfamily B member 1 [ABCB1], ABCG2) were assessed by CCK-8, colony formation, flow cytometry, qRT-PCR and western blot assays. A xenograft tumor model was established and treated with bortezomib for in vivo validation. RESULTS: Compared to H929 cells, U266 and RPMI-8226 cells exhibited elevated CAD and BCL-2 levels as well as reduced drug resistance. Knockdown of CAD or BCL-2 in TP53-mutant MM cells decreased cell proliferation, and the expression of ABCB1, ABCG2, Cyclin D1 and CDK1, while increasing apoptosis, G2/M arrest level and P21 expression. These changes also reduced resistance to bortezomib and doxorubicin. Co-knockdown of CAD and BCL-2 further promoted G2/M arrest, thereby inhibiting proliferation and drug resistance, and facilitating apoptosis. In vivo, co-knockdown of CAD and BCL-2 suppressed the growth of TP53-mutant MM cells and enhanced their sensitivity to bortezomib. CONCLUSIONS: CAD and BCL-2 were highly expressed in TP53-mutant MM cells, and their co-knockdown boosted G2/M cell cycle arrest, thereby preventing cell proliferation, enhancing apoptosis, and reducing drug resistance.
N4BP1 acts as a potent negative regulator of IL-17 signaling by blocking the translation of Act1 mRNA.
Li Y, Xu Z, Zhang X … +9 more , Zhang Z, Ji C, Guo X, Zhang J, Feng P, Mao R, Liu Z, Lu Y, Fan Y
Inflamm Res · 2026 Jan · PMID 41504891 · Publisher ↗
BACKGROUND: Interleukin 17 (IL-17) is a primary pathogenic cytokine, and antibodies blocking its function are clinically approved for treating psoriasis. Although Act1 (TRAF3IP2) is an essential multifunctional adaptor i...
BACKGROUND: Interleukin 17 (IL-17) is a primary pathogenic cytokine, and antibodies blocking its function are clinically approved for treating psoriasis. Although Act1 (TRAF3IP2) is an essential multifunctional adaptor in IL-17 signaling, its regulatory mechanisms remain poorly understood. In this study, the role of endoribonuclease N4BP1 in regulating the IL-17 signaling pathway was characterized. METHODS: N4BP1 was knocked out in both in vivo and in vitro experimental models to detect alterations in the IL-17 signaling pathway. Moreover, the specific mechanism by which N4BP1 exerts its regulatory effect was explored by examining the stability, degradation rate, transcription and translation rate of key proteins. RESULTS: N4BP1 deficiency markedly enhanced IL-17-induced expression of proinflammatory mediators, including CXCL1, CCL20, and MMP9. Unexpectedly, the mRNA stability of CXCL1, CCL20, and MMP9 was largely unaffected by N4BP1 knockout. Further investigation revealed that N4BP1-deficient cells exhibited elevated MAPK phosphorylation, particularly of p38. Pharmacological inhibition of p38 substantially reduced CXCL1, CCL20, and MMP9 levels in N4BP1-deficient cells. This hyperactivation of MAPKs was attributed to an increased protein level of Act1 in N4BP1-deficient cells. Silencing of Act1 with shRNAs in N4BP1-deficient cells greatly diminished the upregulation of CXCL1, CCL20 and MMP9. The elevated Act1 protein level in N4BP1-deficient cells was not due to enhanced Act1 mRNA stability. Instead, polysome profiling demonstrated a pronounced enrichment of Act1 mRNA in the translationally active polysome fraction in N4BP1-deficient cells. In vivo, under pathological stimuli such as IMQ or aging, N4BP1-deficient mice exhibited increased Act1 protein, MAPK phosphorylation, and increased expression of IL-17 downstream genes, including CXCL1, CCL20, and MMP9. Pharmacological inhibition of Act1 ameliorates IMQ-induced skin damage, with a more pronounced therapeutic effect observed in N4BP1 KO mice. CONCLUSIONS: These findings collectively establish that N4BP1 is a potent negative regulator of IL-17 signaling that suppresses the translation of Act1 mRNA.
Cumulative environmental exposures adversely impact social behaviour and are associated with dysregulation of genes and proteins involved in epigenetic, ribosomal, and immune regulation in male mice.
Bucknor MC, Keating BA, Han VX … +13 more , Gloss BS, Dey P, Aryamanesh N, Marshall LL, Graham ME, Dissanayake R, Lau X, Patel S, Petkova SP, Valtchev P, Gururajan A, Dale RC, Hofer MJ
Inflamm Res · 2026 Jan · PMID 41504877 · Full text
OBJECTIVE: This study investigated how cumulative environmental exposures influence offspring behaviour and inflammation-related molecular signatures in the brain and peripheral immune system. METHODS: A novel "triple-hi...
OBJECTIVE: This study investigated how cumulative environmental exposures influence offspring behaviour and inflammation-related molecular signatures in the brain and peripheral immune system. METHODS: A novel "triple-hit" mouse model was developed using C57Bl/6JAusB mice (N = 70), combining preconceptual social stress, antenatal high-fat diet, and a postnatal immune challenge (poly(I:C), 10 mg/kg). At 12 weeks, offspring underwent behavioural tests relevant to neurodevelopmental disorders (NDDs), including the Elevated Plus Maze, 3-Chamber Social Preference, Self-Grooming, and Marble Burying. A composite NDD-risk index was calculated. Single-cell RNA sequencing (scRNA-seq) and bulk proteomics were performed on male triple-hit offspring to identify differentially expressed genes and proteins associated with inflammatory pathways. RESULTS: Male triple-hit offspring showed elevated NDD-related behavioural risk and social deficits, not observed in females. scRNA-seq revealed altered inflammatory and ribosomal pathways in brain glia and peripheral immune cells. Proteomic analysis showed decreased abundance of proteins involved in inflammation, translation, chromatin remodelling, and synaptic function in both brain and blood. CONCLUSION: Combined environmental stressors may drive male-specific behavioural and inflammatory changes relevant to NDDs. The identification of overlapping inflammatory signatures in brain and peripheral immune cells supports a role for shared immune mechanisms in brain-immune axis dysfunction. However, these pathway-level findings should be interpreted as preliminary hypotheses and warrant independent validation to confirm their mechanistic significance.
Dual-function cytokines as modulators of autophagy: reprogramming inflammatory resolution in severe COVID-19.
Khan S, Tang P, Yang P … +2 more , Li J, Wu H
Inflamm Res · 2026 Jan · PMID 41504868 · Publisher ↗
BACKGROUND: Acute respiratory distress syndrome (ARDS) and systemic immune-mediated damage are two of the severe COVID-19 outcomes that are primarily caused by cytokine storms triggered by dysregulated immune responses....
BACKGROUND: Acute respiratory distress syndrome (ARDS) and systemic immune-mediated damage are two of the severe COVID-19 outcomes that are primarily caused by cytokine storms triggered by dysregulated immune responses. The limited benefits of current immunosuppressive treatments highlight the need for mechanistic understanding to direct focused interventions. OBJECTIVE: The dual functions of cytokines in controlling autophagy during SARS-CoV-2 infection are examined in this review, along with the potential for autophagy modulation to limit hyperinflammation and restore immune homeostasis. KEY FINDINGS: Emerging evidence suggests that autophagy critically modulates the balance between pro- and anti-inflammatory cytokines in COVID-19. Through anti-inflammatory feedback mechanisms, cytokines contribute to resolution while promoting inflammation in the early stages. The IRE1α-XBP1 axis is activated by SARS-CoV-2-induced endoplasmic reticulum stress, which increases cytokine production and modifies autophagic flux. Concurrently, extracellular vesicles containing cytokines, damage-associated molecular patterns, and viral components are released as secretory autophagy reroutes cytoplasmic cargo toward multivesicular bodies and amphisomes, increasing paracrine immune activation. Suppressed degradative autophagy and increased secretory autophagy-mediated inflammatory signaling are the hallmarks of this pathological state. CONCLUSIONS: In severe COVID-19, targeted autophagy restoration is a promising therapeutic approach to restore immune responses, reduce excessive inflammation, and encourage the resolution of cytokine storms. Restoring immune homeostasis through more targeted immunointerventions may be made possible by modifying autophagy pathways.
The role of pyroptosis during HIV infection.
Yaseen MM, Abuharfeil NM, Darmani H … +1 more , Shatnawi MN
Inflamm Res · 2026 Jan · PMID 41504820 · Publisher ↗
BACKGROUND: Pyroptosis, a proinflammatory form of programmed cell death, has emerged as a central driver of chronic inflammation, CD4⁺ T cell depletion, and non-AIDS comorbidities in HIV infection. This review synthesize...
BACKGROUND: Pyroptosis, a proinflammatory form of programmed cell death, has emerged as a central driver of chronic inflammation, CD4⁺ T cell depletion, and non-AIDS comorbidities in HIV infection. This review synthesizes current evidence on the molecular mechanisms and pathological consequences of pyroptosis in HIV. METHODS: We conducted a comprehensive analysis of the literature, examining the molecular pathways of pyroptosis triggered by abortive HIV infection, the roles of specific inflammasomes (e.g., AIM2, NLRP3, CARD8) and viral proteins, and the subsequent amplification of inflammation through cytokine release and gut barrier dysfunction. RESULTS: Abortive infection in resting CD4⁺ T cells generates cytosolic viral DNA, activating inflammasomes (primarily AIM2/IFI16) and executing pyroptosis via GSDMD. This process initiates a vicious cycle of immune activation, mucosal damage, microbial translocation, and systemic inflammation, leading to CD4⁺ T cell loss, reservoir persistence, and end-organ damage. Therapeutic targeting of key nodes (e.g., caspase-1, NLRP3, GSDMD) shows promise in preclinical models. CONCLUSION: Pyroptosis is a critical pathological engine in HIV, linking viral infection to chronic immunodeficiency and comorbidities. Adjunctive therapies targeting this pathway may reduce inflammation, preserve immune function, and support strategies toward a functional cure.
The pivotal role and intervention strategies of BMAL1 mediated circadian clock dysregulation in intervertebral disc degeneration.
Chen J, Luo Y, Li F … +7 more , He Y, Zhou Y, Peng L, Liu Y, Liu Z, Song C, Wang Z
Inflamm Res · 2026 Jan · PMID 41498810 · Publisher ↗
BACKGROUND: Intervertebral disc degeneration (IVDD), a primary cause of chronic low back pain, involves extracellular matrix (ECM) degradation and nucleus pulposus cell apoptosis. While traditionally linked to mechanical...
BACKGROUND: Intervertebral disc degeneration (IVDD), a primary cause of chronic low back pain, involves extracellular matrix (ECM) degradation and nucleus pulposus cell apoptosis. While traditionally linked to mechanical stress, inflammation, oxidative stress, and metabolic dysfunction, emerging evidence positions circadian clock disruption as the central hub integrating these factors. Under physiological conditions, the core clock genes BMAL1/CLOCK regulate ECM homeostasis. RESULTS: In IVDD, however, this rhythm is disrupted: abnormal mechanical stress inhibits BMAL1 via the RhoA/ROCK pathway; inflammation (e.g., IL-1β) suppresses BMAL1 transcription through NF-κB, creating a vicious cycle; aging-related oxidative stress and ferroptosis are exacerbated by BMAL1 epigenetic silencing; and metabolic disorders promote NLRP3 inflammasome activation via mTORC1-mediated autophagy suppression and miR-155-dependent BMAL1 mRNA decay. Consequently, circadian dysregulation accelerates ECM breakdown and mitochondrial apoptosis. This synthesis establishes a novel 'circadian-centric' model of IVDD, unifying multifactorial pathogenesis under the framework of rhythm disruption. It reveals precise pathways such as RhoA/BMAL1/ECM, bridging key mechanistic gaps. Therapeutically, this model advocates a paradigm shift from symptomatic management to circadian rhythm reconstruction. Potential strategies include restoring BMAL1 rhythmicity to reverse ECM catabolism, targeting the circadian-inflammatory axis (e.g., melatonin, IL-1β antagonists) to concurrently mitigate inflammation and oxidative damage, and employing chrono-therapeutic interventions such as timed mechanical loading or nighttime drug administration. CONCLUSION: This review provides a foundational rationale for developing chrono-precise diagnostics and treatments, aiming to redefine IVDD management toward endogenous rhythm restoration.
The dual role of ATF3 in myocardial repair through macrophage regulation.
Wang X, He Y, Du Y … +2 more , Li C, Zhang D
Inflamm Res · 2025 Dec · PMID 41454923 · Publisher ↗
OBJECTIVE: Ischemic heart disease (IHD) is one of the leading causes of death globally, and the process of myocardial repair after myocardial infarction (MI) is complex and crucial. Recent studies have underscored the pi...
OBJECTIVE: Ischemic heart disease (IHD) is one of the leading causes of death globally, and the process of myocardial repair after myocardial infarction (MI) is complex and crucial. Recent studies have underscored the pivotal role of cardiac-resident macrophages in the salvage of infarcted myocardium. This literature review summarizes recent findings on the central regulatory function of the activating transcription factor 3 (ATF3) in regulating macrophage behavior and macrophage-cardiomyocyte crosstalk during post-MI myocardial repair. METHODS: A comprehensive review of recent experimental and translational studies was conducted, focusing on ATF3 mediated regulation of macrophage activation, polarization, functional plasticity, and intercellular communication in the context of ischemic heart injury and repair. RESULTS: ATF3, a stress-responsive transcription factor, is a key mediator in oxidative stress and ischemic injury responses across diverse cellular milieus.The complexity of ATF3's role in regulating macrophage involvement in myocardial repair stems from multiple factors: the cell types expressing ATF3 can affect its function; the stage of disease progression may alter ATF3's role; and ATF3's activity is regulated not only at the expression level but also by post-translational modifications such as ubiquitination and SUMOylation. These factors collectively contribute to the intricate regulation of ATF3. Moreover, the origin of macrophages also dictates their multidimensional role in myocardial repair. CONCLUSIONS: The ATF3-macrophage axis represents a critical regulatory network in post-MI myocardial repair. Elucidating its context dependent and cell specific mechanisms may provide novel therapeutic insights for modulating post infarction inflammation and improving cardiac repair outcomes.
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