Inflammasomes are pivotal for the initiation and control of host inflammatory responses. This is particularly important in the respiratory system due to its direct exposure to noxious environmental and infectious stimuli, which can cause local inflammation, tissue damage and impaired function. Inflammasomes are activated by a variety of processes that result in a loss of cellular homeostasis, leading to the oligomerisation of specific innate immune sensors. Inflammasome complex formation then results in a form of programmed cell death known as pyroptosis and release of cleaved active pro-inflammatory cytokines, interleukin (IL)-1β and IL-18, and the subsequent inflammatory cascade. While acute inflammasome activation can be protective in controlling infection, chronic inflammasome activation is detrimental and can lead to irreversible changes in the lung micro-environment such as chronic inflammation, emphysema, lung fibrosis and impaired gas exchange and lung function. In this review, we describe the role of inflammasomes in the pathogenesis of acute and chronic respiratory diseases, highlight currently available preclinical and clinically available therapies that regulate or inhibit inflammasome activation, and outline the use of multi-omics to identify novel inflammasome biomarkers and therapeutics.

Heavy metal-induced toxicity in freshwater fish is driven at the cellular level by reactive oxygen species (ROS) generated through Fenton chemistry, mitochondrial electron transport chain disruption, and competitive displacement of essential metals at sulfhydryl-bearing antioxidant molecules and enzymes. The enzymatic antioxidant battery (superoxide dismutase, catalase, glutathione peroxidase) together with the lipid peroxidation end-product malondialdehyde has been shown in this review to provide a mechanistically grounded and temporally sensitive measure of toxic effect that tracks the Keap1-Nrf2-ARE adaptive cascade far more directly than conventional tissue concentration endpoints can. Subcellular metal partitioning and metallothionein-mediated sequestration, rather than total tissue burden, are demonstrated to govern which fraction of the internal metal pool is biologically reactive; antioxidant responses integrate this bioavailability information automatically. The biphasic dose-response of enzymatic antioxidants, reflecting early Nrf2-driven induction followed by direct metal inactivation at higher exposures, is examined as the mechanistic signature that distinguishes adaptive from damage phases at the individual level. Complementary pro-inflammatory and immunological readouts, including IL-6, TNF-α, NF-κB activation, and altered cytokine balance, are reviewed as second-tier effect markers that broaden the diagnostic envelope beyond pure redox endpoints. Drawing on evidence from industrially impacted river systems, with Pakistan's Indus Basin serving as a representative developing-country case, the Adverse Outcome Pathway paradigm is integrated with classical biomarker science, and a three-stage Bioavailability-Effect Monitoring Framework (BEMF) is proposed as a practical, transferable pathway from exposure measurement to effect-based environmental assessment. The transition from exposure metrics to effect indicators is argued to constitute a necessary conceptual advance for applied toxicology in the protection of aquatic ecosystems under Anthropocene multistressor conditions.

Our previous investigations using antisense-mediated knockdown supported a pathogenic role for the voltage-gated sodium channel isoform Nav1.3 in traumatic brain injury (TBI), yet its downstream mechanisms remain incompletely defined. Here, we observed concurrent elevation of Nav1.3 mRNA and Ca2+ in human brain tissues following TBI. Pharmacological inhibition of Nav1.1/Nav1.3 with ICA-121431 in a controlled cortical impact (CCI) mouse model significantly ameliorated neurological deficits, reduced cerebral edema, downregulated neuronal injury markers (Iba-1, GFAP and iNOS) and pro-inflammatory cytokine (IL-1α, IL-3, IL-6) while upregulating anti-inflammatory IL-13. Notably, ICA-121431 combined with the anti-seizure agent levetiracetam conferred no extra benefit over ICA-121431 monotherapy. In vitro, ICA-121431 protected HT-22 neurons from stretch-induced death, increased FTH1 expression, and decreased NCOA4 levels and LC3BII/I ratio. Lysosomal inhibitor Bafilomycin A1 further elevated both LC3-II/I and FTH1 in injured neurons, confirming that the stretch-induced LC3-II/I rise represents enhanced autophagic flux rather than degradation block. Importantly, combining ICA-121431 with the mitochondrial Na+/Ca2+ exchanger (mNCX) inhibitor ITH12575 yielded greater neuroprotective effects than ICA-121431 alone. Lysosomal blockade failed to induce further accumulation of FTH1 or LC3-II in this combination group, indicating marked attenuation of NCOA4-associated ferritin turnover. Consistently, NCOA4 knockdown recapitulated this protection and restored FTH1 after stretch injury, supporting NCOA4-associated neuronal cell death. Collectively, Nav-channel inhibitor ICA-121431 improved neurological outcomes of TBI mice through reducing neuroinflammation. Concurrent inhibition of Nav-channels and mNCX yielded enhanced in-vitro protection linked to attenuated NCOA4-associated ferritin turnover. These insights provided a mechanistic basis for novel TBI therapeutic strategies targeting sodium‑calcium homeostasis.

Hepatic cytochrome P450 2E1 (CYP2E1) is an important P450 enzyme involved in the metabolism of numerous xenobiotics. Notably, it contributes to the metabolic activation of many pro-carcinogenic and toxic compounds, thereby playing a critical role in human health and disease development. Previous studies suggest that gut microbiota modulate hepatic CYP2E1 expression; however, the microbiota's effects are inconsistent, and the underlying mechanisms remain unknown. Here, we show that the gut microbiota suppress hepatic CYP2E1 expression, at least in part, through the gut microbial metabolite indole-3-propionic acid (IPA). Hepatic CYP2E1 expression was significantly increased in germ-free and antibiotic-treated mice compared with conventionally raised mice, indicating that the gut microbiota reduce hepatic CYP2E1 expression. Furthermore, we found that IPA, a gut microbial metabolite, accumulates at high levels in the livers of conventionally raised mice but is barely detectable in germ-free or antibiotic-treated mice. Finally, IPA treatment reduced CYP2E1 expression both in liver cells and in mice. Collectively, these findings demonstrate that the gut microbiota suppress hepatic CYP2E1 expression, at least in part, through microbial metabolites, particularly IPA. These findings suggest a novel mechanism by which the gut microbiota regulate host metabolism and human health.

Environmental ingestion of polystyrene nanoplastics (PNPLs) raises critical public health concerns, yet their impacts on colorectal cancer (CRC) remain obscure. In this study, network toxicology, and in vitro validation were integrated to evaluate the molecular mechanisms linking PNPLs to CRC. We identified 154 overlapping targets by integrating GEO-derived differentially expressed genes with PNPLs-predicted targets and CRC-associated genes, which are enriched in pathways associated with cancer signaling, apoptosis, oxidative stress, and inflammation. Using protein-protein interaction network, along with two machine learning algorithms (LASSO and Random Forest), we identified seven hub genes in which the expression of these genes was corroborated by the CRC database of TCGA, the CRC dataset of GEO, and the RT-qPCR analysis on HCT-116 cells. Molecular docking demonstrated the significant binding affinities between PNPLs and six hub targets. In vitro experiments with HCT-116 cells revealed PNPLs dose- and time-dependent cytotoxicity. Additionally, PNPLs induced oxidative stress by significant reactive oxygen species (ROS) accumulation, collapse of mitochondrial membrane potential, and decrease of SOD, GPx and CAT activity. Furthermore, PNPLs caused apoptosis while concurrently pronounced pro-inflammatory responses by exciting the release of pro-inflammatory cytokines and mediators, including IL-6, IL-1β, TNF-α, NO, and PGE2. This study suggests the complex toxicity effects of PNPLs on CRC and supports the need for further research into nanoplastics as a potential environmental risk factor for CRC.

The paradigm shift toward patient-centric precision medicine has established personalized cancer vaccines (PCVs) as a key strategy for eliciting tumor-selective immunity. However, traditional cell-based PCVs face significant translational barriers, including manufacturing complexity and safety concerns. While tumor-derived extracellular vesicles (TDEVs) offer a promising cell-free alternative that recapitulates the parental tumor's antigenic landscape, their therapeutic efficacy is frequently antagonized by intrinsic immunosuppressive cargo. Here, we report ChimeraVax, a chimeric vesicular vaccine platform engineered by covalently conjugating TDEVs with Lactobacillus acidophilus-derived membrane vesicles (LAMVs) via bio-orthogonal, copper-free click chemistry. In this hybrid assembly, the TDEVs serve as a comprehensive antigen reservoir, while the LAMVs provide potent natural adjuvanticity that bypasses TDEV-mediated immunosuppression. In vitro, ChimeraVax facilitated the synchronized delivery of tumor antigens and immunostimulatory molecules to dendritic cells, significantly enhancing antigen uptake and pro-inflammatory signaling. In a murine model of aggressive triple-negative breast cancer, subcutaneous administration of ChimeraVax coordinated both innate and adaptive immune responses, yielding robust antitumor efficacy. Notably, ChimeraVax showed strict antigen dependence, selectively suppressing matched lesions with minimal effects on mismatched tumors, highlighting its specificity and translational potential as a modular personalized cancer vaccine platform.

Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a life-threatening infectious disease, yet current antibiotic-centered therapies remain insufficient to achieve satisfactory therapeutic outcomes. Herein, a lysostaphin-bioengineered cascade nanoreactor, LO-PDA/Zn@CA, is developed for the integrated treatment of MRSA pneumonia. This system consists of cinnamaldehyde (CA)-loaded, Zn2+-chelated polydopamine nanoparticles coated with lysostaphin-engineered bacterial outer membrane vesicles. Upon reaching MRSA-infected lung lesions, CA disrupts the biofilm matrix and compromises bacterial membranes, thereby weakening extracellular protective barriers. Zn2+ subsequently activates surface-displayed lysostaphin to specifically hydrolyze pentaglycine cross-bridges within the MRSA peptidoglycan cell wall, further breaching bacterial integrity and promoting intrabacterial penetration of CA and Zn2+. The released Zn2+ induces lethal DNA damage-associated responses, collectively amplifying bactericidal efficacy through a stepwise antibacterial cascade. In parallel, the PDA/Zn nanocore scavenges excessive reactive oxygen species, suppresses glycolytic reprogramming, and downregulates H3K27ac-dependent transcription of pro-inflammatory genes, thereby attenuating macrophage M1 polarization and mitigating pulmonary inflammatory injury. In vitro and in vivo studies demonstrate that LO-PDA/Zn@CA effectively eliminates planktonic MRSA, disrupts established biofilms, and alleviates MRSA-induced pulmonary inflammation with favorable biosafety. By integrating pathogen-specific bacterial eradication with inflammation resolution in a cascade manner, this work provides a versatile nanotherapeutic strategy for the treatment of drug-resistant MRSA pneumonia.

CircRNAs are critical regulators in retinal neural tissues, yet the functions of most retina-enriched members remain unknown. circMettl9, highly expressed in the mouse retina, shows declining expression during postnatal development. Sustained circMettl9 overexpression in adult retinas via AAV-mediated subretinal injection triggers Müller gliosis, secretion of pro-inflammatory cytokines and retinal functional impairment: elevated GFAP levels and abnormal electroretinogram (ERG) responses were detected, while overt structural abnormalities were absent. Mechanistically, circMettl9 drives mitochondrial dysfunction, oxidative stress elevation and caspase-3 activation to promote retinal cell apoptosis via the circMettl9/miR-10a-5p/Bcl2l11 axis. Our study is the first to clarify the biological role of circMettl9 in mouse retina, providing novel theoretical insights and potential therapeutic targets for retinal diseases.

Giant cell arteritis (GCA) is a large-vessel vasculitis predominantly affecting individuals over 50 years, with a peak incidence between 70 and 80 years. Its pathogenesis involves complex immunological cascades triggered by vascular dendritic cell activation, recruitment of CD4⁺ T cells and monocytes, T helper lymphocyte polarization, and vascular remodeling driven by myofibroblasts and fibroblasts. Growing evidence implicates cellular senescence (particularly in vascular smooth muscle cells, fibroblasts, endothelial cells, and immune cells) in the pathophysiology of GCA. Senescent cells (SC) accumulate in affected arteries and display a senescence-associated secretory phenotype (SASP), producing pro-inflammatory cytokines, chemokines, and matrix metalloproteinases, thereby perpetuating inflammation and tissue injury. Senotherapeutics (agents targeting SC) are broadly classified into senolytics, which induce SC apoptosis, and senomorphics, which suppress SASP without eliminating SC. Candidate senolytics include fisetin, quercetin, curcumin, and dasatinib, which also show anti-inflammatory, antioxidant, and vascular-protective effects, although some may cause adverse vascular consequences. Senomorphics such as resveratrol, kaempferol, apigenin, epigallocatechin gallate, rapamycin, metformin, and ruxolitinib modulate NF‑κB, mTOR, JAK/STAT, and sirtuin pathways, potentially reducing vascular inflammation, restoring immune balance, and preventing remodeling, besides acting on aging-associated modifications. As current treatments primarily suppress inflammation and may not fully target age-related mechanisms contributing to persistent vascular injury, investigating cellular senescence as a potentially actionable component of GCA biology is timely. Key challenges include selecting optimal agents, timing, dosing, and duration, while avoiding adverse vascular effects. The aim of this review was to identify potential clinical and translational applications of senotherapeutic compounds for GCA to guide future research in this field.

ObjectiveAtopic dermatitis (AD) involves complex immune dysregulation, with the IL-18 BP/IL-18 axis emerging as a critical yet underexplored regulator of pathological inflammation. While α-boswellic acid (α-BA) has shown therapeutic promise in AD, its role in regulating the IL-18 BP/IL-18 axis under the inflammatory microenvironment is unclear. This study aimed to elucidate whether α-BA could restore IL-18 BP/IL-18 homeostasis and thus suppress inflammation while preserving immune defense.MethodsA two-sample Mendelian randomization (MR) analysis using summary-level genome-wide association data was conducted to evaluate the potential causal contribution of circulating IL-18 levels to AD susceptibility. DNFB-induced AD mouse model and TNF-α/IFN-γ-stimulated HaCaT cells were used to evaluate α-BA's effects on barrier function, cytokine profiles, and IL-18 BP/IL-18 axis modulation. RNA sequencing (RNA-seq) was employed to identify the critical mediator of α-BA.ResultsMR analysis showed a statistically significant but modest association between genetically predicted circulating IL-18 levels and AD risk (OR=1.003, P<0.05). α-BA restored epidermal barrier integrity in AD mice and normalized serum IgE and IL-13 levels. In HaCaT cells, α-BA treatment rebalanced the IL-18 BP/IL-18 axis and reduced pro-inflammatory cytokines. In addition, α-BA inhibited MyD88/NF-κB signaling, whereas blocking the IL-18 BP/IL-18 axis abolished this effect. RNA-seq identified metalloendopeptidase (MME) as a candidate molecule associated with α-BA treatment, and pharmacological inhibition of MME attenuated the effects of α-BA on the IL-18 BP/IL-18 axis.Conclusionsα-BA may alleviate AD by modulating the IL-18 BP/IL-18 axis and downstream MyD88/NF-κB signaling pathways. MME may contribute to α-BA-mediated regulation of the IL-18 BP/IL-18 axis.

Vision-language models (VLMs) are increasingly explored for clinical interpretation tasks. Electrocardiographic (ECG) identification of acute coronary occlusion (ACO) is a high-risk application requiring accurate pattern recognition, and medical VLM performance on this task remains poorly characterised outside benchmark datasets.,Methods: A medical-domain VLM (MedGemma 1.5) was tested between 30 January and 22 February 2026 using 15 de-identified 12‑lead ECGs: 14 source-labelled ACO or high-risk occlusion phenotypes and one normal control. Each ECG was submitted with a standardised prompt requesting a structured interpretation and overall concern level (low, intermediate, or high), without iterative prompting. The same ECGs were submitted to a general-purpose VLM comparator (Gemini 3.1 Pro).,Results: MedGemma 1.5 assigned low concern in 8/15 cases (53%) and intermediate concern in 7 (47%); no case reached high concern, including among the 14 high-risk ECGs. It under-recognised ST-segment elevation, failed to integrate reciprocal and territorial patterns, and missed hyperacute T-wave morphology. Conduction abnormalities and quantitative parameters were assessed inconsistently. The comparator assigned high concern to all 14 high-risk cases but also to the normal control, citing an incorrect ECG pattern.,Conclusion: A medical VLM showed clinically important interpretation failures and did not escalate concern in any high-risk ECG. A general-purpose comparator was more consistent across high-risk cases but misclassified the normal control, suggesting some failure modes may not be modelspecific. These findings support task-specific validation and governance before multimodal AI is deployed in time-critical cardiovascular settings.