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This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI. The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups. Except the Sham group, a model of CLP-induced sepsis was established in other groups. After 24 h, the indicators related to kidney injury in blood samples were detected. The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored. Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined. Finally, the expression of proteins related to the TLR4/NF-κB signaling pathway was observed by western blot. Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (  < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (  < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (  < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP (  < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group. TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.

Non-alcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to other severe liver diseases, yet treatment options are limited. Endoplasmic reticulum (ER) stress is an important pathogenetic mechanism of NASH and plays a key role in tandem steatosis as well as liver inflammation. This study aims to develop a progressive NASH model through sustained lipid accumulation and to elucidate its molecular mechanism through IRE1α/TRAF2 complex. Male SD rats were fed a high-fat diet (HFD) for 4, 8, and 12 weeks to induce progressive NASH. MRNA sequencing and PPI analysis were used to screen core genes. Transmission electron microscopy, immunofluorescence staining, ELISA, qRT-PCR, and Western blotting were used at each time point to compare differences between each index of progressive NASH at 4, 8, and 12 weeks. Sustained lipid accumulation led to structural disruption of the ER, a reduction in ER number, and an increase of lipid droplet aggregation in hepatocytes. Persistent lipid accumulation led to a persistent increase in mRNA and protein expression of the IRE1α/TRAF2 complex, IKK/IκB/NF-κB signaling pathway and ASK1/JNK1 signaling pathway, and TNF-α, IL-1β, and IL-6 also continued to increase. Persistent lipid accumulation led to a persistent exacerbation of ER stress and inflammation in progressive NASH via the IRE1α/TRAF2 complex.

Osteoarthritis (OA) is a chronic inflammatory disease primarily characterized by cartilage damage, and its pathological mechanisms remain to be elucidated. This study aimed to identify potential therapeutic targets for OA and to further explore their associated molecular mechanisms. Candidate OA-associated genes were identified by integrating differential expression analysis, WGCNA, and PPI network analysis. Diagnostic marker genes were subsequently determined using machine-learning algorithms (RF, LASSO, and SVM-RFE) and further validated by ROC analysis and nomogram modeling. Single-cell sequencing analyses were conducted to characterize the temporal dynamics of these marker genes across the developmental trajectory of OA chondrocytes. Both in vitro and in vivo experiments were performed to confirm the expression of key molecules and the activation of relevant pathways. In addition, berberine, a natural isoquinoline alkaloid with anti-inflammatory potential, was selected as a candidate compound to evaluate its interaction with THY1 by molecular docking and molecular dynamics simulation. A total of 19 candidate OA-associated hub genes were identified. By integrating three machine-learning algorithms, THY1 was determined as a diagnostic marker gene for OA, and ROC curves and a nomogram model confirmed its favorable diagnostic/predictive performance. Single-cell sequencing further suggested a gradual upregulation of THY1 during chondrocyte development in OA. Both in vitro and in vivo experiments supported the feasibility of THY1 as a potential therapeutic target. Computational simulations demonstrated favorable binding between berberine and THY1. This study suggests that THY1 may serve as a diagnostic biomarker for OA and may be involved in disease progression through its association with the NF-κB signaling pathway. Moreover, our computational simulations provide preliminary and predictive structural insights into the potential interaction between berberine and THY1, thereby expanding possible research directions for berberine-based approaches in OA.

Aims TANK‐binding kinase 1 (TBK1) is involved in regulating the pathological process of a variety of inflammatory diseases in the central nervous system. However, its role and underlying molecular mechanisms in spinal cord injury (SCI) remain largely unknown. Methods We employed the TBK1 inhibitor amlexanox (ALX) to address this question. An in vivo clip‐compressive SCI model and in vitro lipopolysaccharide (LPS)‐induced astrocyte inflammation model were established to examine the effects of TBK1 inhibition on the expression of proinflammatory cytokines. Results In this study, we found that TBK1 and TBK1‐medicated innate immune pathways, such as TBK1/IRF3 and noncanonical NF‐κB signaling, were activated in astrocytes and neurons after SCI. Furthermore, inhibition of TBK1 by ALX alleviated neuroinflammation response, reduced the loss of motor neurons, and improved the functional recovery after SCI. Mechanistically, inhibition of TBK1 activity promoted the activation of the noncanonical NF‐κB signaling pathway and inhibited p‐IRF3 activity in LPS‐induced astrocytes, and the TBK1 activity was required for astrocytic activation through yes‐associated protein (YAP) signaling after SCI and in LPS‐induced astrocytes inflammation model. Conclusion TBK1‐medicated innate immune pathway in astrocytes through YAP signaling plays an important role in the pathogenesis of SCI and inhibition of TBK1 may be a potential therapeutic drug for SCI. ALX treatment inhibits TBK1‐YAP pathway and activates the noncanonical NF‐κB signaling pathway in astrocytes, which results in the suppression of reactive astrocytes, including reduce of cell proliferation, decrease of mRNA level of IL‐6, IL‐1β, reduce of inflammatory cell infiltration, and promotion of the degradation of p100 and the translation of NF‐κB p52‐RELB heterodimers into the nucleus, and inhibition of phosphorylation of IRF3 and reduce of YAP nuclear transfer.

IκB Kinase (IKK)α is required for activation of an alternative NF‐κB signaling pathway based on processing of the NF‐κB2/p100 precursor protein, which associates with RelB in the cytoplasm. This pathway, which activates RelB:p52 dimers, is required for induction of several chemokine genes needed for organization of secondary lymphoid organs. We investigated the basis for the IKKα dependence of the induction of these genes in response to engagement of the lymphotoxin β receptor (LTβR). Using chromatin immunoprecipitation, we found that the promoters of organogenic chemokine genes are recognized by RelB:p52 dimers and not by RelA:p50 dimers, the ubiquitous target for the classical NF‐κB signaling pathway. We identified in the IKKα‐dependent promoters a novel type of NF‐κB‐binding site that is preferentially recognized by RelB:p52 dimers. This site links induction of organogenic chemokines and other important regulatory molecules to activation of the alternative pathway.

PTEN-induced putative kinase 1 (PINK1), a master regulator of mitophagy, is implicated in mitochondrial homeostasis, yet its role in knee osteoarthritis (OA) pathogenesis remains unclear. The present study investigated the mechanisms by which PINK1 modulates chondrocyte senescence during OA progression. Utilizing a destabilization of the medial meniscus-induced OA murine model, decreased PINK1 expression, impaired mitochondrial function and suppressed mitophagy were observed in OA cartilage. In vitro, lipopolysaccharide-induced chondrocyte senescence was exacerbated by PINK1 knockdown but mitigated by PINK1 overexpression, which restored mitophagy and reduced senescence-associated β-galactosidase activity, reactive oxygen species accumulation and mitochondrial membrane potential collapse. RNA sequencing and mechanistic studies identified the p38 MAPK/NF-κB pathway as a downstream target; PINK1 knockdown amplified the phosphorylation of p38 MAPK/NF-κB, promoting mitochondrial dysfunction and senescence. By contrast, pharmacological inhibition of p38 MAPK/NF-κB rescued these effects in PINK1-deficient chondrocytes. Collectively, PINK1 attenuated OA progression by suppressing chondrocyte senescence via inhibition of the p38 MAPK/NF-κB pathway, highlighting its potential as a therapeutic target for OA management.

At least eight types of ubiquitin chain exist, and individual linkages affect distinct cellular processes. The only distinguishing feature of differently linked ubiquitin chains is their structure, as polymers of the same unit are chemically identical. Here, we have crystallized Lys 63‐linked and linear ubiquitin dimers, revealing that both adopt equivalent open conformations, forming no contacts between ubiquitin molecules and thereby differing significantly from Lys 48‐linked ubiquitin chains. We also examined the specificity of various deubiquitinases (DUBs) and ubiquitin‐binding domains (UBDs). All analysed DUBs, except CYLD, cleave linear chains less efficiently compared with other chain types, or not at all. Likewise, UBDs can show chain specificity, and are able to select distinct linkages from a ubiquitin chain mixture. We found that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO (NF‐κB essential modifier) binds to linear chains exclusively, whereas the NZF (Npl4 zinc finger) domain of TAB2 (TAK1 binding protein 2) is Lys 63 specific. Our results highlight remarkable specificity determinants within the ubiquitin system.

Neuroinflammatory processes mediated by microglial activation and subsequent neuronal damage are the hallmarks of traumatic brain injury (TBI). As an inhibitor of the macrophage-inducible C-type lectin (Mincle)/spleen tyrosine kinase (Syk) signaling pathway, BAY61-3606 (BAY) has previously demonstrated anti-inflammatory effects on some pathological processes, such as acute kidney injury, by suppressing the inflammatory macrophage response. In the present study, the potential effects of BAY on microglial phenotype and neuroinflammation after TBI were investigated. BAY (3 mg/kg) was first administered into mice by intraperitoneal injection after TBI induction in vivo and microglia were also treated with BAY (2 µM) in vitro. The levels of inflammatory factors in microglia were assessed using reverse transcription-quantitative PCR and ELISA. Cortical neuron, myelin sheath, astrocyte and cerebrovascular endothelial cell markers were detected using immunofluorescence. The levels of components of the Mincle/Syk/NF-κB signaling pathway [Mincle, phosphorylated (p)-Syk and NF-κB], in addition to proteins associated with inflammation (ASC, caspase-1, TNF-α, IL-1β and IL-6), apoptosis (Bax and Bim) and tight junctions (Claudin-5), were measured via western blotting and ELISA. Migration and chemotaxis of microglial cells were evaluated using Transwell and agarose spot assays. Neurological functions of the mice were determined in vivo using the modified neurological severity scoring system and a Morris water maze. The results of the present study revealed that the expression levels of proteins in the Mincle/Syk/NF-κB signaling pathway (including Mincle, p-Syk and p-NF-κB), inflammatory cytokines (TNF-α, IL-1β and IL-6), proteins involved in inflammation (ASC and caspase-1), apoptotic markers (Bax and Bim) and the tight junction protein Claudin-5 were significantly altered post-TBI. BAY treatment reversed these effects in both the cerebral cortex extract-induced cell model and the controlled cortical impact mouse model. BAY was also revealed to suppress activation of the microglial proinflammatory phenotype and microglial migration. In addition, BAY effectively attenuated TBI-induced neurovascular unit damage and neurological function deficits. Taken together, these findings provided evidence that BAY may inhibit the Mincle/Syk/NF-κB signaling pathway in microglia; this in turn could attenuate microglia-mediated neuroinflammation and improve neurological deficits following TBI.

Overactive bladder (OAB) is a common condition that affects lower urinary tract symptoms and markedly affects the physical and mental health of individuals. While the cause of OAB is unclear, some studies suggest a possible link to psychological factors, particularly anxiety. Despite this, research on the connection between anxiety and OAB is limited. The present study aimed to explore anxiety-induced OAB by analyzing clinical data and identifying key genes and pathways in vivo, ultimately providing new insights for diagnosing and treating OAB. Clinical data were analyzed to explore the relationship between anxiety and OAB. A chronic restraint stress model was used to induce anxiety, with histological scoring and cystometry assessing bladder function. Bladder transcriptomics identified key genes and pathways in OAB development. Differences in oxidative stress and NF-κB pathway activity were validated using immunohistochemistry, enzyme-linked immunosorbent assay and quantitative PCR. Clinical data showed a positive link between overactive bladder symptom scores and general anxiety disorder scale-7, with higher urination urgency scores in OAB patients with anxiety. Analysis confirmed anxiety as an independent risk factor for OAB. In vivo experiments showed that anxiety induced OAB-like symptoms in mice through oxidative stress and NF-κB pathway activation, with RNA sequencing revealing key hub genes included heat shock protein 90 (Hsp90) aa1, Hsp90ab1 and Hsp90b1. The present study demonstrated that anxiety may precipitate the onset of OAB by activating oxidative stress and the NF-κB signaling pathway. Hsp90 may serve as a potential biomarker for diagnosing anxiety-induced OAB. Retrospectively registered on 1 April 2025, The present study received the identifier ChiCTR2500100548 from the Chinese Clinical Trial Registry.

Background Interleukin‐1β (IL‐1β) is a pro‐inflammatory cytokine mainly produced by monocytes and macrophages with a wide range of biological effects. Evidence has shown that IL‐1β plays a vital role in the process of apoptosis; however, the specific mechanisms, by which IL‐1β induces apoptosis, vary due to different cellular and experimental conditions. Therefore, this present reviewstudy aimed to systematically review the association between the molecular mechanisms of IL‐1β‐induced apoptosis in pathological processes and the role of signaling pathways. This article also sought to briefly investigate the potential of signaling pathway‐targeted therapy in the prevention and treatment of disease. Methods This is a literature review article. The present discourse aim is first to scrutinize and assess the available literature on IL‐1β and apoptosis. The relevant studies using the keywords of “IL‐1β‐induced apoptosis” and “signaling pathways” were searched in the databases of PubMed, Scopus, Google Scholar, and Web of Science. Gathered relevant material, and extracted information was then assessed. Results IL‐1β can induce apoptosis in various types of cells under different external stimuli via the mitochondrial pathway, death receptor pathway and endoplasmic reticulum pathway, and that the different pathways are often interconnected. The NF‐kB signaling pathway, p38MAPK, and JNK signaling pathways mainly play a proapoptotic part, and the ERK1/2 pathway has a bidirectional role in regulating apoptosis, while activation of the PI3K‐Akt signaling pathway can inhibit apoptosis. Conclusion This review indicates that IL‐1β‐induced apoptosis plays an important role in pathogenesis and development of pathology of many inflammatory diseases. Elucidating the role of the signaling pathways will aid the development of targeted therapeutic treatments. Evidence has shown that interleukin‐1β (IL‐1β) plays a vital role in the process of apoptosis. This paper reviews the molecular mechanisms of IL‐1β‐induced apoptosis in pathological processes, focusing on the role of signaling pathways. This article also briefly describes the potential of signal pathway‐targeted therapy in the prevention and treatment of disease, using the application of signal pathways in the treatment of disc degeneration and osteoarthritis as examples.