MAVS operates downstream of cytosolic viral RNA sensing and coordinates antiviral responses through type I interferon and nuclear factor kappa B (NF-κB) signaling. The review examines how this signaling intersects with activation of the NLRP3 inflammasome. In the pathway described, MAVS contributes to inflammasome activation, which is followed by caspase-1 activation, gasdermin D cleavage, cytokine release and pyroptotic cell death. These linked events provide a mechanistic explanation for how viral recognition can generate both antiviral activity and inflammatory responses. Rather than assigning MAVS a single role, the review presents it as a signaling hub whose effects depend on the cellular context and the downstream pathway that becomes engaged.

The clearest HIV-1-specific contrasts in the review emerge from the different outcomes in myeloid cells, macrophages and quiescent CD4+ T cells. In myeloid cells and macrophages, HIV-1 has evolved several mechanisms that dampen MAVS-dependent antiviral responses. This suppression can weaken innate controls on replication and create conditions favorable to viral replication and persistence. The review also emphasizes that mechanisms demonstrated in HIV-1 infection models should not be conflated with findings established in other viral systems. Its central model is therefore not that every viral sensing event converges on MAVS, but that HIV-1 regulates innate pathways in a cell type-dependent manner, suppressing antiviral activity in some compartments while allowing or promoting inflammatory pathways in others.

Abortive infection of quiescent CD4+ T cells follows a distinct route in the evidence summarized by the review. Rather than requiring MAVS, this response uses IFI16-dependent, caspase-1-mediated pyroptosis. The authors describe this MAVS-independent pathway as a major contributor to CD4+ T-cell depletion and chronic inflammation. The distinction matters because it separates MAVS-dependent signaling from inflammasome activation that can occur without MAVS. The review also discusses emerging evidence for CARD8-mediated inflammasome activation, identifying it as another potential route through which innate pathways may complement antiviral defense while influencing HIV-1 pathogenesis. These findings broaden the network under consideration beyond a single MAVS-centered axis and show that different inflammasome pathways can be associated with distinct outcomes.

The review places these mechanistic observations in the broader problem that HIV-1 is not cured by antiretroviral therapy because latent viral reservoirs persist and chronic immune activation continues alongside infection. Its proposed significance is that understanding how MAVS, inflammasomes and pyroptosis interact across different cell types may open possibilities for host-directed approaches intended to limit viral persistence and reduce chronic inflammation. That remains a research direction, not an established treatment or demonstrated clinical benefit. The evidence reviewed is primarily mechanistic and draws on multiple experimental systems; the authors explicitly distinguish observations made in HIV-1 models from evidence derived from other viral infections and from connections that still need validation in HIV-1.

Subject of Research: Cell-specific MAVS-dependent and independent inflammasome signaling in HIV-1 infection

Article Title: MAVS signaling in HIV-1 infection: linking innate viral sensing to inflammasome activation, pyroptosis and viral persistence

Article References: Nesci, S., Glogowski, P. A., Cugliari, A., Trombetti, F., & Algieri, C. (2026). MAVS signaling in HIV-1 infection: linking innate viral sensing to inflammasome activation, pyroptosis and viral persistence. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09119-5

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09119-5

Keywords: HIV-1, MAVS, Inflammasomes, Pyroptosis, Innate immunity, CD4+ T cells, NLRP3, IFI16, CARD8, Viral persistence, signaling, infection

The team began with microarray data from two public peripheral-blood cohorts. The larger training dataset, GSE66360, contained 49 people with acute myocardial infarction and 50 healthy controls, while the independent validation dataset, GSE61144, contained seven patients and ten controls. Comparing patients with controls in the training cohort identified 477 differentially expressed genes, including 351 with increased expression and 126 with decreased expression. Intersecting this list with a previously published set of 822 genes encoding regulators of 20 protein post-translational modifications produced 17 candidate genes. Functional enrichment connected the candidates with processes including polyubiquitination, ubiquitin-ligase complexes, secretory-granule lumens and viral-response pathways, indicating that much of the emerging signal involved protein turnover and immune regulation.

To narrow the 17 candidates, the researchers applied three complementary machine-learning feature-selection methods: support vector machine recursive feature elimination, extreme gradient boosting and random forest. Their overlapping selections included GABARAPL1, PELI1, TNFAIP3 and NLRP3. TNFAIP3 did not show consistently significant differential expression between the two public datasets, so it was removed. The remaining three genes were consistently increased in acute myocardial infarction samples in both cohorts, and each had a receiver operating characteristic area under the curve above 0.80 in the training and validation sets. These values describe discrimination between patients and healthy controls in the analyzed data; they do not establish performance for diagnosing acute myocardial infarction in a general clinical population.

A deep neural network built around the three biomarkers achieved an area under the curve of 0.963 in the full training dataset. To reduce the risk of overestimating performance, the authors also used fivefold stratified cross-validation, generating an out-of-fold area under the curve of 0.894, with a 95% confidence interval of 0.832 to 0.957. A logistic-regression model using the same biomarkers reached 0.826, with a 95% confidence interval of 0.736 to 0.916. The difference between the two models was not statistically significant, with P equal to 0.1269. The comparison therefore shows that the neural network produced a higher point estimate under cross-validation, not that it was demonstrably superior to logistic regression.

Gene-set enrichment linked GABARAPL1 to 88 pathways, PELI1 to 84 and NLRP3 to 76, with shared signals involving messenger RNA splicing, Leishmania infection and chemokine signaling. The Leishmania result is a pathway-level annotation from human gene sets rather than evidence of parasitic infection. At the cellular level, the analysis estimated the abundance of 28 immune populations and found significant differences between patients and controls for 23 subsets, including activated B cells, activated CD4-positive T cells and activated dendritic cells. Macrophages and neutrophils were strongly correlated, with a Spearman coefficient of 0.87 and P below 0.001. GABARAPL1, PELI1 and NLRP3 were each most strongly associated with plasmacytoid dendritic cells, with coefficients of 0.66, 0.69 and 0.65, respectively.

The biological interest of the three markers lies in the different processes with which they are already associated. GABARAPL1 encodes a protein linked to autophagosome formation and maturation, a pathway involved in cellular stress responses and clearance of damaged components. PELI1 encodes an E3 ubiquitin ligase that participates in nuclear factor-kappa-B and JAK/STAT signaling and is connected with inflammatory responses and macrophage polarization. NLRP3 encodes a core component of the inflammasome, whose activation is associated with caspase-1 signaling and maturation of the inflammatory cytokines interleukin-1 beta and interleukin-18. Prior work discussed by the authors also links ubiquitination, deacetylation and phosphorylation of NLRP3 to myocardial injury. The present study measured messenger RNA, however, rather than the modifications of NLRP3 or other target proteins.

Database-based network reconstruction suggested possible layers of regulation around the biomarkers. The researchers predicted 15 transcription factors for GABARAPL1, seven for PELI1 and 14 for NLRP3. Predicted microRNAs numbered 10 for GABARAPL1, six for PELI1 and one for NLRP3, and these links were used to assemble an interaction network containing 1,393 microRNA–long non-coding RNA pairs. Such networks are computational hypotheses assembled from known or predicted binding relationships; they do not demonstrate that any factor changes the expression or activity of a biomarker in acute myocardial infarction. The analysis also linked the three genes to 80, 29 and 42 candidate compounds, respectively, before selecting representative pairs for molecular docking.

Docking simulations gave 1,4-chrysenequinone a score of −7 kilocalories per mole with GABARAPL1 and −8.9 kilocalories per mole with PELI1. Calcitriol produced a score of −10.1 kilocalories per mole with NLRP3. More negative scores were interpreted by the authors as stronger predicted binding affinity. These calculations do not establish that the compounds can safely or effectively treat acute myocardial infarction, nor do they capture metabolism, concentration, tissue delivery or effects on the intact cardiovascular system. The authors appropriately identified cellular and animal experiments as necessary steps for testing whether the proposed compounds alter biomarker function or cardiac outcomes.

Clinical expression validation used reverse-transcription quantitative PCR on blood from five patients with acute myocardial infarction and five healthy controls recruited at the Second Hospital of Hebei Medical University. All three transcripts were significantly higher in the patient group, with P below 0.001, consistent with the direction of the transcriptomic findings. The result is encouraging but limited by the very small sample, the selection of healthy rather than clinically suspected non-AMI controls and the absence of direct protein measurements. The study also used public cohorts with modest sample sizes, which may not represent the full variation in ethnicity, geography, comorbidity or clinical presentation. Proteomic and post-translational-modification assays, larger independent cohorts and appropriately designed diagnostic studies will therefore be needed before the biomarkers can be considered clinically validated or used as therapeutic targets.

Subject of Research: Transcriptomic screening of protein post-translational-modification regulators in acute myocardial infarction

Article Title: Exploring biomarkers and regulatory mechanisms associated with 20 protein post-translational modifications in acute myocardial infarction based on transcriptomics

Article References: Zhang, J., Li, B., Yang, M., Lu, J., Jiang, H., & Chen, F. (2026). Exploring biomarkers and regulatory mechanisms associated with 20 protein post-translational modifications in acute myocardial infarction based on transcriptomics. Frontiers in Cardiovascular Medicine, 13, 1848328. https://doi.org/10.3389/fcvm.2026.1848328

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1848328

Keywords: acute myocardial infarction, blood biomarkers, transcriptomics, post-translational modification, GABARAPL1, PELI1, NLRP3, immune infiltration, molecular docking, machine learning, Exploring, biomarkers

The research team, led by Chengfeng Pan and colleagues at Cangnan Hospital of Wenzhou Medical University in China, took an unusually disciplined approach to a common pitfall in genomics. Rather than pooling datasets from different microarray platforms and hoping for the best, they analyzed four Gene Expression Omnibus datasets study by study, without any cross-platform batch harmonization. The discovery cohort, GSE59867, contained 111 admission samples from patients with ST-segment elevation myocardial infarction and 46 samples from patients with stable coronary artery disease. Three further cohorts, GSE48060, GSE60993, and GSE66360, totaling 348 participants across the study, served as fully independent validation sets. This design choice matters: by refusing to merge technically incompatible data, the researchers ensured that any signal surviving validation was biological rather than an artifact of preprocessing.

The first layer of analysis painted a vivid picture of the immune landscape in heart attack. Using marker-based scoring of nine immune cell programs, the team found that neutrophil and classical monocyte signatures were markedly elevated in STEMI patients, with Cliff’s delta effect sizes of 0.635 and 0.611 respectively and false discovery rates below 10^-8. In mirror image, natural killer cell and CD8 T-cell programs were suppressed. This myeloid surge with lymphoid retreat is exactly what cardiologists would predict from the biology of ischemia-reperfusion: dying heart muscle releases danger-associated molecular patterns that trigger neutrophil infiltration, monocyte extravasation, and macrophage activation. When that inflammatory wave clears debris and scaffolds repair, it is beneficial; when it persists, it drives fibrosis, maladaptive remodeling, and progressive cardiac dysfunction.

To connect genes to this immune picture, the researchers applied weighted gene co-expression network analysis, or WGCNA, to the 1,000 most variable genes in the discovery cohort. The network resolved into eight modules, and the largest, containing 215 genes, showed the strongest association with STEMI status, with a point-biserial correlation of 0.591 and an FDR of 2.97 x 10^-15. Gene ontology testing revealed that inflammatory response was the dominant biological theme within this module, with 20 of its 215 genes belonging to that pathway at an FDR of 2.41 x 10^-10. Hub topology analysis confirmed that genes most connected within the module were also the ones most strongly tied to disease status, a pattern that lends biological coherence to the statistical signal.

The centerpiece of the study, however, is the machine learning pipeline that distilled this complexity into a compact diagnostic index. The team used nested cross-validation, a design that strictly separates feature selection from performance estimation to prevent information leakage and overfitting. Within each of 25 outer test folds, genes were ranked by Welch-test p-value and the top eight selected; four algorithms, including L2-regularized logistic regression, linear support vector machines, random forest, and gradient boosting, then produced predictions. Three genes, BAX, EDA2R, and MCEMP1, were selected in every single outer fold, a striking consistency. The final fixed model settled on eight genes: BAX, EDA2R, MCEMP1, SOCS3, ASGR2, RNASE1, ADM, and KPNA5.

The performance numbers are eye-catching. In the discovery cohort, the repeated out-of-fold area under the receiver operating characteristic curve, a standard measure of diagnostic discrimination, reached 0.984 for logistic regression and 0.986 for the linear SVM, with a Brier score of 0.080 indicating good calibration. More importantly, the index transported to independent data: validation AUCs were 0.863 in GSE48060, 0.876 in GSE66360, and 0.655 in GSE60993. The authors are candid about the weaker result. GSE60993 mixed STEMI and NSTEMI patients, used whole blood rather than the PBMC or enriched cell preparations of the other cohorts, and contained only 24 samples, all factors that plausibly diluted the myeloid inflammatory signal the index was built to detect. A fourth dataset, GSE62646, yielded an AUC of 0.995 but was treated only as a technical sensitivity analysis because participant overlap with the discovery cohort could not be excluded.

What do the eight genes actually do? The study weaves them into a mechanistic narrative of sterile cardiac inflammation. BAX is a pro-apoptotic regulator of cell death, fitting for a disease defined by cardiomyocyte necrosis. EDA2R, which carried the largest positive coefficient in the final model with an odds ratio of 2.72 per standardized unit, is increasingly linked to aging and degenerative signaling. MCEMP1 marks mast cells and myeloid populations, while SOCS3 is a feedback inhibitor of cytokine signaling that spikes during inflammatory activation. ASGR2, RNASE1, ADM, and KPNA5 round out the panel with roles spanning hepatic clearance, extracellular RNA degradation, hypoxia adaptation, and nuclear transport. Notably, six of the eight genes retained the same direction of disease association across all five cohorts examined, though BAX and EDA2R reversed direction in two, a reminder that cross-cohort heterogeneity is real even when overall performance holds.

Pathway analysis added further depth. Among discovery genes ranked by test statistic, the strongest positive Hallmark signal was epithelial-mesenchymal transition, but IL-6/JAK/STAT3 signaling, inflammatory response, hypoxia, reactive oxygen species response, and TNF-alpha/NF-kB signaling all ranked positively as well, forming a connected network of leading-edge genes. A single-cell dataset, GSE121893, provided cellular context showing that the model genes display distinct expression patterns across endothelial cells, smooth-muscle cells, fibroblasts, and macrophages, with MCEMP1 concentrated in macrophages. The authors are careful to note that this dataset contained no actual AMI specimens, so it offers context rather than proof of AMI-specific localization.

The team also ran laboratory experiments to ground the computational findings in wet-lab reality. Using ATCC-authenticated THP-1 monocytes differentiated into macrophage-like cells and stimulated with lipopolysaccharide and ATP to activate the NLRP3 inflammasome, plus EA.hy926 endothelial cells subjected to hypoxia-reoxygenation, they measured four prespecified inflammatory transcripts by RT-qPCR. All four rose significantly: CXCL10 increased 3.82-fold, IL6 4.15-fold, NLRP3 2.94-fold, and CASP1 3.47-fold, each across three independent biological replicates. Because these transcripts were chosen as inflammasome-axis markers rather than members of the eight-gene model itself, the experiment corroborates the inflammatory program underlying AMI rather than directly validating the diagnostic index, a distinction the authors draw explicitly.

The study is equally forthright about its limits. Two exploratory outcome analyses, predicting six-month heart failure progression in 17 patients and 18-month recurrent events in 31, produced AUCs of 0.819 and 0.569 respectively, results the authors label descriptive only, given tiny event counts and the absence of patient-level censoring data. No Kaplan-Meier curves or hazard ratios were computed, and an exploratory two-subtype clustering of STEMI patients showed a numerical but non-significant difference in heart failure events. The researchers call for prospective validation with protocol-standardized blood sampling and blinded outcome adjudication before any clinical use. Still, the core achievement stands: a leakage-controlled, multi-cohort-validated blood-based gene index that captures the immune fingerprint of heart attack, built entirely on transparent, reproducible analysis of public data. If prospective studies confirm its accuracy, such a signature could one day complement troponin testing and help identify which patients carry the inflammatory profiles most likely to benefit from emerging immune-targeted therapies, from IL-6 receptor blockade to NLRP3 inhibitors now advancing through clinical development.

Subject of Research: A machine learning-derived eight-gene blood transcriptomic index for diagnosing acute myocardial infarction and characterizing its inflammatory immune response

Article Title: Cross-cohort blood transcriptome analysis identifies an eight-gene diagnostic index and inflammatory programs in acute myocardial infarction

Article References: Pan, C., Chen, Z., Li, J., Xie, S., & Fan, X. (2026). Cross-cohort blood transcriptome analysis identifies an eight-gene diagnostic index and inflammatory programs in acute myocardial infarction. Frontiers in Cardiovascular Medicine, 13, Article 1904246. https://doi.org/10.3389/fcvm.2026.1904246

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1904246

Keywords: acute myocardial infarction, blood transcriptomics, machine learning, diagnostic gene signature, inflammasome, NLRP3, immune response, WGCNA, biomarker validation, precision cardiology, CXCL10, heart failure

The NLRP3 inflammasome is a multiprotein sensor that sits at the crossroads of innate immunity and neurodegeneration. When activated, it assembles into a complex that processes pro-caspase-1 into active caspase-1, which in turn cleaves pro-interleukin-1β into its mature, pro-inflammatory form. In the central nervous system, this cascade drives microglial activation, the inflammatory state of the brain’s resident immune cells that has been implicated in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative conditions. Because NLRP3-driven neuroinflammation can amplify neuronal damage, pharmacologically damping this pathway has become a major therapeutic goal, and the search for inhibitors has intensified in recent years.

To explore whether Angelica gigas could contribute to that effort, the researchers prepared three different preparations: a conventional water extract, an ethanol extract, and a residue-derived ethanol extract obtained from the biomass left behind after aqueous extraction. Chemical profiling showed that despite the prior water treatment, the residual material retained meaningful levels of pyranocoumarins, and the subsequent ethanol extraction yielded the residue extract with the highest concentrations of two key compounds, decursin and decursinol angelate. This result challenges the assumption that water extraction strips a plant of its most valuable chemistry, and it suggests that a second, solvent-based pass over the same biomass can recover bioactive molecules that would otherwise be discarded.

The team then tested the three preparations in BV2 microglial cells, a widely used model of brain-resident immune cells, stimulated with lipopolysaccharide, a bacterial molecule that reliably triggers inflammatory signaling. The residue-derived ethanol extract significantly reduced the expression of NLRP3, the adaptor protein ASC, cleaved caspase-1, and mature interleukin-1β. In other words, the extract did not merely blunt a single downstream marker; it suppressed the inflammasome at multiple points along its activation axis. The effect was more pronounced with the residue extract than with the conventional preparations, consistent with its enriched pyranocoumarin content.

To move beyond cell culture, the researchers turned to a mouse model of LPS-induced neuroinflammation. Animals treated with the residue extract showed reduced microglial activation in the brain, indicating that the anti-inflammatory activity observed in vitro translates to living tissue. This in vivo confirmation matters because many compounds that look promising in isolated cells fail to reproduce their effects in whole organisms, where absorption, metabolism, and tissue distribution complicate the picture.

Seeking a molecular explanation for the activity, the researchers focused on decursin, one of the two dominant pyranocoumarins in the residue extract. Using molecular docking, they predicted that decursin could bind directly to the NLRP3 protein. They then confirmed measurable binding experimentally with surface plasmon resonance, a technique that detects physical association between a small molecule and its protein target in real time. Decursin treatment also reduced NLRP3 expression and interleukin-1β production in the cell model, supporting a direct functional link between the compound and the inflammasome pathway.

To validate that NLRP3 was the relevant target rather than an incidental binding partner, the researchers used MCC950, a well-characterized selective NLRP3 inhibitor, as an intervention tool. The comparison with MCC950 helped clarify the association between decursin and NLRP3 signaling, reinforcing the conclusion that the residue extract’s anti-neuroinflammatory activity operates through this specific inflammasome rather than through a generic anti-inflammatory effect. This kind of target validation is important because many natural products show broad anti-inflammatory activity, and pinpointing the actual molecular mechanism distinguishes a true pharmacological lead from a nonspecific suppressant.

The study’s broader significance lies in its approach to resource valorization. Herbal medicine production generates enormous quantities of extraction residue worldwide, and recent reviews have highlighted the environmental and economic costs of discarding this biomass. The Angelica gigas findings suggest that a simple sequential extraction strategy, water first and ethanol second, can convert what would be waste into a standardized, bioactive extract. Because the residue extract outperformed the conventional preparations in pyranocoumarin content and inflammasome suppression, the sequential approach may actually improve on traditional single-pass extraction rather than merely recover leftovers.

Angelica gigas has a long history in traditional Korean medicine, and previous research has documented its anti-inflammatory, neuroprotective, and cognitive-enhancing properties. Decursin and decursinol angelate have been studied for their molecular mechanisms in inflammatory diseases, and pyranocoumarins from the plant have shown neuroprotective potential against glutamate-induced hippocampal cell death. The current work adds a specific inflammasome mechanism to this pharmacological profile, connecting the plant’s traditional use to a contemporary molecular target that is actively being pursued by pharmaceutical researchers.

For now, the findings remain at the preclinical stage, and the researchers note that further work would be needed to establish dosing, safety, and efficacy in humans. But the study offers a concrete example of how a circular approach to medicinal plant processing can yield both environmental and pharmacological dividends. By treating extraction residue as a resource rather than a byproduct, the researchers have identified a sustainable source of NLRP3-targeting compounds and demonstrated that the chemistry left behind after conventional processing may be more valuable than the chemistry that is taken out first.

Subject of Research: Angelica gigas residue extracts suppress NLRP3 inflammasome activation and neuroinflammation

Article Title: Pyranocoumarin-enriched residue extracts of Angelica gigas suppress NLRP3 inflammasome activation and neuroinflammation

Article References: Lim, H.-S., Seo, C.-S., Kim, D.-S., Son, E., Jeon, W.-Y., Jin, S. E., Jang, J.-H., & Park, G. (2026). Pyranocoumarin-enriched residue extracts of Angelica gigas suppress NLRP3 inflammasome activation and neuroinflammation. Molecular Biology Reports, 53(1), Article 1732. https://doi.org/10.1007/s11033-026-12951-z

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12951-z

Keywords: Pyranocoumarin-enriched, residue, extracts, Angelica, gigas, suppress, NLRP3, inflammasome, activation, neuroinflammation, scientific research

Febuxostat is a highly selective nonpurine inhibitor of xanthine oxidase, the enzyme that generates reactive oxygen species during purine metabolism. Approved for chronic hyperuricemia associated with gout, the drug has demonstrated antioxidant, anti-inflammatory, anti-apoptotic, and tissue-protective effects in numerous experimental disease models. Because oxidative stress is increasingly recognized as a key contributor to psoriasis pathogenesis, with excessive reactive oxygen species driving lipid peroxidation, DNA damage, mitochondrial dysfunction, and activation of inflammatory pathways, the researchers reasoned that inhibiting xanthine oxidase in the skin might interrupt this destructive cycle. Until now, however, the potential of topical febuxostat for psoriasis had never been investigated.

To test the idea, the team prepared ointments containing 0.5, 1, and 2 percent febuxostat by weight, dissolved in dimethyl sulfoxide and incorporated into a white soft paraffin base using the fusion method. Each formulation was characterized for homogeneity, drug content uniformity, spreadability, viscosity, pH, and physical stability over 60 days of storage. Drug content ranged from 98.42 to 99.16 percent of theoretical values across the three concentrations, pH values sat between 6.21 and 6.27, and all formulations remained physically stable throughout the storage period, confirming consistent pharmaceutical quality before animal testing began.

The investigators then induced psoriasis-like dermatitis in adult male BALB/c mice by applying 62.5 milligrams of commercially available 5 percent imiquimod cream to shaved dorsal skin for seven consecutive days. Forty-eight mice were randomly assigned to six groups of eight animals each: a normal control receiving petroleum jelly, an imiquimod control treated with ointment base alone, a positive control treated with clobetasol propionate 0.05 percent cream, and three groups treated with the 0.5, 1, or 2 percent febuxostat ointments. Treatments were applied topically approximately 30 minutes after imiquimod administration each day, and disease severity was scored daily by a blinded investigator using a modified PASI-like system assessing erythema, scaling, and skin thickening.

The results were striking. Imiquimod produced progressive erythema and scaling, with cumulative clinical scores climbing steadily over the treatment week, whereas febuxostat attenuated these manifestations in a concentration-dependent manner. By day seven, the 2 percent formulation had reduced scaling scores to 0.5 and erythema scores to zero, outcomes comparable to or better than those achieved with clobetasol. Histopathological examination of hematoxylin and eosin-stained skin sections reinforced the clinical picture. Imiquimod-treated mice showed marked epidermal hyperplasia, hyperkeratosis, parakeratosis, elongation of the dermoepidermal junction, and dense inflammatory cell infiltration, with epidermal thickness increasing from 38.6 to 112.4 micrometers. The 2 percent febuxostat ointment reduced epidermal thickness to 63.7 micrometers and earned median hyperplasia and infiltration scores of just 1 on the semiquantitative scale, approaching the near-normal architecture seen in clobetasol-treated animals.

Biochemical analyses revealed that the clinical improvements were accompanied by coordinated restoration of the skin’s redox balance. Imiquimod application raised tissue levels of malondialdehyde, a marker of lipid peroxidation, from 1.52 to 5.91 nanomoles per milligram of protein, and nitric oxide from 14.8 to 42.7 micromoles per liter, while superoxide dismutase activity collapsed from 84.7 to 31.4 units per milligram and reduced glutathione fell from 8.92 to 3.18 micromoles per milligram. Treatment with 2 percent febuxostat reversed these changes dramatically, lowering malondialdehyde to 1.89 nanomoles per milligram and nitric oxide to 17.6 micromoles per liter, while restoring superoxide dismutase to 79.1 units per milligram and glutathione to 8.21 micromoles per milligram, values statistically indistinguishable from the normal control group for the antioxidant parameters.

The anti-inflammatory effects were equally pronounced. Imiquimod drove tissue concentrations of tumor necrosis factor-alpha, interleukin-17A, and interleukin-23 to 88.6, 79.2, and 82.4 picograms per milligram of protein, respectively, compared with 24.8, 18.5, and 20.3 picograms per milligram in normal controls. These cytokines sit at the heart of the interleukin-23/interleukin-17 immune axis that drives psoriasis initiation and maintenance, as activated dendritic cells produce interleukin-23, promoting the differentiation of T helper 17 cells that release interleukin-17A and tumor necrosis factor-alpha, fueling epidermal hyperplasia and sustained inflammation. The 2 percent febuxostat formulation suppressed all three cytokines to 29.7, 25.4, and 27.1 picograms per milligram, approaching normal levels and outperforming the 0.5 and 1 percent formulations, which showed progressively weaker effects.

At the molecular level, the researchers used quantitative real-time PCR to measure expression of NFE2L2, the gene encoding NRF2, the master regulator of cellular antioxidant responses, and NLRP3, a central component of inflammasome-associated inflammatory signaling. Imiquimod downregulated NFE2L2 mRNA to 0.38-fold of normal levels while upregulating NLRP3 mRNA to 4.82-fold, indicating impairment of antioxidant defenses and amplification of inflammasome-related signaling. Febuxostat modulated both genes in a concentration-dependent fashion, with the 2 percent formulation restoring NFE2L2 expression to 0.95-fold and reducing NLRP3 expression to 1.28-fold, values approaching those of the normal control group and comparable to or exceeding the molecular effects of clobetasol.

The authors are careful to note that these transcriptional changes do not by themselves establish direct activation of the NRF2 pathway or inhibition of the NLRP3 inflammasome. The study evaluated the genes only at the mRNA level, without measuring NRF2 protein expression, nuclear translocation, or transcriptional activity, and without assessing NLRP3 protein, inflammasome assembly, caspase-1 activity, or maturation of interleukin-1beta and interleukin-18. Additional limitations include the absence of in vitro drug-release and ex vivo skin permeation studies, the potential contribution of dimethyl sulfoxide, which was present in all febuxostat formulations as a co-solvent and penetration enhancer, and the lack of long-term topical safety or systemic exposure data. Nevertheless, the parallel improvement in clinical severity, histopathology, oxidative stress biomarkers, cytokine levels, and gene expression supports a coordinated antioxidant and anti-inflammatory effect of the treatment.

Because febuxostat may offer a nonsteroidal pharmacological approach through inhibition of xanthine oxidase, in contrast to the glucocorticoid receptor-dependent mechanisms of clobetasol, the findings open a genuinely novel avenue for psoriasis research. The apparent therapeutic similarity between the 2 percent febuxostat ointment and clobetasol propionate across several measured outcomes should be interpreted in terms of the experimental results rather than as evidence of equivalent mechanisms or clinical efficacy, and direct comparison of long-term safety profiles remains beyond the scope of the current work. Still, the study provides a compelling rationale for future pharmaceutical, mechanistic, and translational investigations of topical febuxostat as a potential nonsteroidal candidate for psoriasis, and the prospect that a widely used gout medication might be repurposed as a skin treatment is likely to capture attention well beyond the laboratory.

Subject of Research: Pharmacology

Article Title: Topical febuxostat attenuates imiquimod-induced psoriasiform dermatitis and modulates NFE2L2 ( NRF2 )/ NLRP3 mRNA expression

Article References: Alamir, H. T., Albahadly, W. K., Al-Zubaidy, H. F. S., Sahib, A. S., Altrufi, M. H., & Hamza, N. (2026). Topical febuxostat attenuates imiquimod-induced psoriasiform dermatitis and modulates NFE2L2 (NRF2)/NLRP3 mRNA expression. Pharmacia, 73, Article e207442. https://doi.org/10.3897/pharmacia.73.e207442

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e207442

Keywords: febuxostat, psoriasis, NRF2, NLRP3, oxidative stress, imiquimod, topical treatment, mouse model, Topical, attenuates, imiquimod-induced, psoriasiform

The review, led by Rahul A. Sachdeo of Krishna Institute of Medical Sciences in Karad, India, together with colleagues from Krishna Institute of Pharmacy and the Gaurishankar Institute of Pharmaceutical Education and Research, weaves together decades of immunology research into a single framework. Its central claim is provocative: the same inflammasome complexes that protect us in the first hours after injury can, when they stay active too long, drive the persistent inflammation, tissue destruction, and scarring that turn an ordinary wound into a lifelong medical problem.

Inflammasomes are multi-protein sensors of the innate immune system, the body’s ancient first line of defense. Several family members matter in wounded skin, including NLRP3, AIM2, NLRC4, NLRP1, and Pyrin. Each sensor detects a different danger signal, from bacterial molecules to stray DNA released by damaged cells. Once triggered, an inflammasome assembles into an activation platform that switches on inflammatory caspases, most notably caspase-1. Caspase-1 then performs two critical tasks: it cleaves the inactive precursor forms of the signaling molecules interleukin-1 beta and interleukin-18 into their mature, biologically active versions, and it promotes a fiery form of programmed cell death called pyroptosis, which proceeds through pores formed by the protein gasdermin D.

In the short term, this machinery is lifesaving. Pyroptosis flushes intracellular pathogens out of infected cells, mature interleukin-1 beta recruits immune cells to clear debris and fight infection, and the resulting inflammatory signals help coordinate the earliest phases of tissue repair. Wound healing itself is a highly choreographed sequence of four overlapping stages: hemostasis, inflammation, proliferation, and remodeling. Transient inflammasome activity is what allows the wound to transition smoothly from the inflammatory phase into the proliferative phase, when new tissue is built. The trouble begins when the switch never gets flipped off.

Sustained or dysregulated inflammasome activation keeps caspase-1 running and pyroptosis churning, flooding the wound environment with inflammatory cytokines and cell contents. The result is persistent inflammation, ongoing tissue injury, and aberrant remodeling of the extracellular matrix, the protein scaffold that gives tissue its structure. Over time, this chaotic environment pushes the wound toward fibrosis, an excessive deposition of scar-like matrix, and toward the chronic wound state in which regeneration grinds to a halt. The review emphasizes that distinguishing inflammasome molecules’ roles as mechanistic mediators of this damage from their potential as measurable biomarkers and therapeutic targets is now a central task for the field.

What makes the review timely is its focus on specific molecular fingerprints. The authors catalog a broad panel of candidate biomarkers spanning the entire inflammasome pathway: the sensors themselves, the adaptor proteins that link them to caspases, the inflammatory caspases, pyroptosis-related mediators such as gasdermin D, the cytokines they release, and oxidative stress-associated factors. Oxidative stress is deeply entangled with inflammasome biology, since reactive oxygen species are known to regulate NLRP-family sensors, creating a crosstalk loop in which metabolic and inflammatory signals amplify one another. Molecules such as thioredoxin-interacting protein, which links high glucose to NLRP3 activation, illustrate how metabolic dysfunction can be read out through inflammasome-associated markers.

The review also highlights how modern genomic technologies are transforming biomarker discovery. Transcriptomic, proteomic, and metabolomic approaches can identify candidate molecules at scale, while single-cell RNA sequencing and spatial transcriptomics add two crucial dimensions: which cells are producing the signal, and where in the wound they are located. This cell-specific and spatial information matters enormously in wounds, where keratinocytes, macrophages, and fibroblasts exchange signals across a heterogeneous landscape. Recent work showing that diabetic wound keratinocytes can induce macrophage NLRP3 expression through interleukin-1 receptor signaling, and that interferon-gamma priming enables NLRP3 activation in human keratinocytes, underscores how cell-type-specific these interactions are. Such resolution, the authors argue, can improve biomarker validation and allow clinicians to stratify wound states far more precisely than current visual assessment allows.

One of the review’s most clinically valuable contributions is its comparison across wound types. Diabetic foot ulcers, pressure ulcers, venous leg ulcers, burn wounds, and fibrotic scars all involve inflammasome-mediated mechanisms, but each is driven by a distinct trigger. In diabetes, metabolic dysfunction and high glucose drive NLRP3 activation; in pressure ulcers, ischemia-reperfusion injury generates oxidative stress that aggravates tissue damage; in venous leg ulcers, venous hypertension sustains inflammatory pressure on the tissue; in burns, thermal injury releases damage-associated molecular patterns that activate inflammasomes, and studies in mouse models suggest NLRP3 activity is actually required for healing after burns; and in fibrotic scars, dysregulated tissue remodeling, often intertwined with transforming growth factor beta signaling, locks the wound into a scar-producing program. Understanding these shared and condition-specific pathways could allow therapies to be tailored to the biology of each wound rather than applied generically.

The therapeutic implications are already taking shape. Small-molecule NLRP3 inhibitors, first validated as potential treatments for inflammatory diseases, are being explored for diabetic wounds, and nanotechnology-based delivery systems and stimulus-responsive hydrogels are being designed to modulate inflammasome activity directly at the wound site. Meanwhile, smart wound dressings that monitor biological parameters in real time could eventually incorporate inflammasome-derived markers, turning a passive bandage into a diagnostic device. Cytokine ratios measured in chronic wound swabs, such as interleukin-1 beta relative to its natural antagonist the interleukin-1 receptor antagonist, have already been proposed as potential biomarkers of wound healing stage and infection status, hinting that the clinic may not be far behind the laboratory.

Challenges remain before inflammasome biomarkers reach the bedside. Inflammasome activation is context-dependent, and a marker that signals danger in one wound type may signal productive repair in another, as the burn studies suggest. Validation will require large, well-characterized patient cohorts and multi-omic profiling across wound types and healing stages. Yet the framework laid out in this review offers something chronic wound medicine has lacked: a mechanistic, measurable, and spatially resolved language for describing why some wounds heal and others stall. If that language can be translated into routine diagnostics, the millions of patients caught in the cycle of chronic inflammation and scarring may finally get the precision care their wounds demand.

Subject of Research: The role of inflammasome-derived biomarkers in wound healing, chronic inflammation, fibrosis, and precision therapeutics

Article Title: Inflammasome-derived biomarkers in wound healing: linking tissue repair, chronic inflammation, fibrosis, and precision therapeutics

Article References: Sachdeo, R. A., Khanwelkar, C., Shete, A., Patil, S. J., & Pawar, N. B. (2026). Inflammasome-derived biomarkers in wound healing: linking tissue repair, chronic inflammation, fibrosis, and precision therapeutics. Molecular Biology Reports, 53(1), Article 1610. https://doi.org/10.1007/s11033-026-12783-x

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12783-x

Keywords: inflammasome, NLRP3, wound healing, chronic wounds, pyroptosis, biomarkers, fibrosis, caspase-1, diabetic foot ulcers, interleukin-1 beta, single-cell RNA sequencing, precision medicine

NLRP3, short for NOD-like receptor pyrin domain 3, is a pattern-recognition protein that assembles into a multi-protein machine known as an inflammasome. When the sensor detects danger signals, ranging from cholesterol crystals to products of cellular damage, it triggers the enzyme caspase-1, which in turn processes the inflammatory messengers interleukin-1 beta and interleukin-18. Caspase-1 also cleaves Gasdermin D, producing an N-terminal fragment that punches pores in the cell membrane and initiates a fiery form of cell death called pyroptosis. Inflammasome hyperactivation is already infamous in human medicine: inherited gain-of-function mutations in NLRP3 cause cryopyrin-associated periodic syndromes, devastating autoinflammatory diseases. What has been missing is direct in vivo evidence showing what happens when this same sensor is chronically overactive specifically within the smooth muscle cells of the artery wall.

To answer that question, the team, led by Yun-Ting Wang, Xiang Li, and Yang Zhang, engineered a mouse carrying an Nlrp3 gain-of-function mutation, the L351P variant, exclusively in vascular smooth muscle cells by combining the knock-in allele with a Myh11-driven Cre recombinase. This model, dubbed Nlrp3-SMKI, allowed the investigators to isolate the contribution of smooth muscle-intrinsic inflammasome signaling from the contributions of immune cells and endothelium. The researchers then subjected these animals and control mice to partial ligation of the carotid artery under hypercholesterolemic conditions, a well-established surgical model that produces disturbed blood flow, endothelial dysfunction, and rapid development of neointimal lesions that mimic human restenosis and early atherosclerosis.

The results were striking even before any surgical injury was applied. In unligated arteries of the mutant mice, the team already detected elevated caspase-1 activation-associated signaling, indicating that the hyperactive inflammasome was quietly simmering within the vessel wall under baseline conditions. When the carotid artery was partially ligated, this inflammatory activity surged further, revealing that the gain-of-function mutation primed the smooth muscle cells to mount an exaggerated response to vascular stress. In other words, the mutation did not merely add inflammation after injury; it fundamentally lowered the threshold at which the arterial wall responded to danger.

Downstream of caspase-1, the pathological cascade unfolded across multiple fronts. The ligated arteries of the mutant mice showed heightened vascular inflammation, marked by increased expression of VCAM1, an adhesion molecule that recruits inflammatory cells, and by greater accumulation of macrophage-associated signals within the vessel wall. The researchers also documented enhanced Gasdermin D and Gasdermin D N-terminal-associated signaling, the molecular signature of pyroptotic cell injury, together with increased numbers of TUNEL-positive cells indicating cell death. These findings weave smooth muscle cells into the inflammatory fabric of the lesion in a way that earlier cell-culture studies had suggested but could not prove in a living organism.

The functional consequence was a dramatically worsened structural outcome. Neointimal lesion growth was significantly exacerbated in the mutant animals, as measured by increased intimal area and an elevated intima-to-media ratio, the standard metrics of pathological vessel thickening. Because the only genetic difference between the experimental and control groups was the hyperactive Nlrp3 allele confined to smooth muscle cells, the study provides compelling causal evidence that smooth muscle-intrinsic inflammasome signaling is not a passive bystander in intimal hyperplasia but an active driver of lesion expansion.

Perhaps the most clinically provocative finding concerned lipid metabolism. The injured arteries of the mutant mice accumulated more lipid and displayed foam cell-like remodeling, including within regions containing alpha-smooth muscle actin-positive cells. Foam cells, the cholesterol-engorged cells that define atherosclerotic plaques, have traditionally been associated with macrophages, but a growing body of literature shows that vascular smooth muscle cells can undergo phenotypic switching and adopt foam cell characteristics, becoming a major and underappreciated cellular component of plaques. The new data indicate that NLRP3 hyperactivation within smooth muscle cells actively promotes this lipid-laden transformation in the injured arterial wall, linking inflammasome signaling directly to one of the hallmarks of atherosclerosis.

Beneath these observations, the researchers uncovered a possible mechanistic explanation involving cellular housekeeping. The mutant arteries showed reduced expression of transcription factor EB, or TFEB, the master regulator of lysosomal biogenesis and autophagy, along with altered expression of lysosome- and autophagy-related markers. TFEB orchestrates the cell’s waste-disposal and recycling systems, and previous work by some of the same investigators showed that activating TFEB ameliorates smooth muscle dedifferentiation and neointima formation in mice fed a high-fat diet. The new findings suggest that NLRP3 hyperactivation may disrupt these stress-adaptive pathways, leaving smooth muscle cells less able to digest damaged proteins, clear lipids, and maintain their contractile identity during vascular remodeling. The association between inflammasome overactivity and impaired lysosomal-autophagic function offers an attractive framework for understanding how inflammation and metabolic dysfunction reinforce each other in the diseased artery.

The clinical implications are considerable. Cardiovascular disease remains the leading cause of death worldwide, and while statins and the anti-inflammatory antibody canakinumab have demonstrated that taming inflammation reduces cardiovascular events, broadly suppressing the immune system carries risks. The new study suggests that a more precise strategy, targeting NLRP3-associated signaling specifically within vascular smooth muscle cells, could limit restenosis after stenting or bypass grafting and slow plaque progression without wholesale immunosuppression. Several NLRP3 inhibitors are already in development for other inflammatory conditions, and the mouse model created by the Houston and Richmond team provides a platform for testing whether such compounds can keep injured arteries open. As with all murine studies, translation to human patients will require careful validation, and the authors note that their data establish associations alongside causal effects that warrant further mechanistic dissection. Still, by pinpointing a single molecular sensor in a single cell type as a linchpin of arterial thickening, the work transforms our understanding of what happens inside a vessel wall after injury, and it offers a concrete molecular bullseye for the next generation of cardiovascular anti-inflammatory therapies.

Subject of Research: The role of vascular smooth muscle NLRP3 inflammasome hyperactivation in arterial intimal hyperplasia and restenosis

Article Title: Vascular smooth muscle-specific NLRP3 hyperactivation exacerbates arterial intimal hyperplasia in mice

Article References: Wang, Y.-T., Moura, A. K., Zuo, R., Gao, W., McConnell, B. K., Li, G., Li, P.-L., Li, X., & Zhang, Y. (2026). Vascular smooth muscle-specific NLRP3 hyperactivation exacerbates arterial intimal hyperplasia in mice. Journal of Molecular Medicine, 104(1), Article 116. https://doi.org/10.1007/s00109-026-02724-3

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02724-3

Keywords: NLRP3, inflammasome, vascular smooth muscle cells, intimal hyperplasia, restenosis, caspase-1, Gasdermin D, pyroptosis, TFEB, lysosome-autophagy, foam cells, atherosclerosis

The challenge the researchers set out to solve is one of geometry and biology combined. Most laboratory studies of Kawasaki disease rely on flat, two-dimensional sheets of endothelial cells, the thin lining that coats the inside of blood vessels. Such cultures are easy to grow and easy to analyze, but they bear little resemblance to the real thing. A coronary artery is a hollow, curved, multilayered tube in which endothelial cells interface with blood on one side and smooth muscle cells wrap the exterior, providing structural support. Animal models, particularly mice, have been used for decades, but the differences between mouse and human vascular and immune biology often limit how well findings translate to the clinic. The team, led by Xuting Zhang and colleagues at Wenzhou Medical University and collaborating institutions, hypothesized that recreating the true three-dimensional, bilayered architecture of a coronary artery would yield a far more faithful model of the disease.

Their manufacturing method of choice was microfluidic coaxial bioprinting, an elegant technique that exploits the same principle as a pipe within a pipe. The researchers assembled a device from glass capillaries and injection needles, aligning an inner capillary concentrically inside an outer one. Two fluids were pumped through this coaxial nozzle: an outer bioink containing 10 percent gelatin methacryloyl, or GelMA, blended with polyethylene glycol diacrylate, or PEGDA, and an inner sacrificial stream of 10 percent polyvinyl alcohol. When the co-flowing streams emerged from the capillary tip, ultraviolet light at 405 nanometers triggered photopolymerization of the outer hydrogel, locking in a continuous tube. The uncrosslinked PVA core was then simply washed away, leaving behind a hollow hydrogel microfiber with an open lumen running its entire length.

The precision achievable with this setup is remarkable. By adjusting the relative flow rates of the inner and outer fluids, the team could dial in the dimensions of the fibers at will. Holding the inner flow at 15 milliliters per hour and raising the outer flow from 15 to 35 milliliters per hour shifted the ratio of inner to outer diameter from about 65.5 percent down to 58.4 percent, while the outer diameter swelled from roughly 712 to 911 micrometers. Reversing the adjustment, by accelerating the inner stream while holding the outer one constant, enlarged both the overall caliber and the relative lumen. Throughput was equally impressive: a single milliliter of bioink yielded between roughly 4 and 6.5 meters of continuous hollow fiber, depending on the diameter chosen, underscoring the scalability of the approach.

Mechanical tuning came from the PEGDA content. Three formulations containing 2.5, 5, and 7.5 percent PEGDA in 10 percent GelMA produced hydrogels with Young’s moduli of approximately 73, 153, and 221 kilopascals respectively, and rheological testing confirmed the same trend in storage modulus. Swelling behavior plateaued within 24 hours, and the matrices retained more than 95 percent of their mass after a day in culture medium, yet dissolved completely within 24 hours when exposed to the enzyme collagenase, showing that degradation is enzymatically controllable rather than a product of passive hydrolysis. Importantly, the softest formulation, 10 percent GelMA with 2.5 percent PEGDA, proved best for early cell attachment, because PEGDA, while excellent for structural strength, tends to resist cell adhesion. That formulation was selected for all subsequent vascular constructs.

With the scaffold optimized, the researchers populated it with human cells in a deliberate sequence. First, human umbilical vein endothelial cells, or HUVECs, at a density of 10 million cells per milliliter were injected into the lumen and allowed 72 hours to engraft, forming a continuous endothelial monolayer with uniform circumferential alignment. Then human coronary artery smooth muscle cells, at 100 million cells per milliliter, were applied to the outer surface, where they colonized the exterior and formed a distinct smooth muscle layer. Confocal microscopy of the cytoskeleton and immunostaining confirmed the architecture: the endothelial marker CD31 lined the luminal surface, while alpha-smooth muscle actin was confined to the outer layer, faithfully reproducing the bilayered organization of a native coronary artery.

Crucially, the model was more than a structural mimic. When the team perfused fluorescent dextran molecules of 4 and 70 kilodaltons through the lumen, the endothelialized constructs allowed far less leakage into the surrounding hydrogel than acellular controls, demonstrating that the engineered endothelium functioned as a selective barrier to both small solutes and large plasma proteins, just as a real vessel does. As a positive control, exposure to the inflammatory molecule TNF-alpha for six hours triggered a cascade of endothelial activation: elevated lactate dehydrogenase release signaling membrane injury, increased oxidative stress, upregulation of the adhesion molecules ICAM-1, VCAM-1, and E-selectin, a surge of inflammatory cytokines and chemokines including IL-1beta, IL-6, IL-8, CX3CL1, CCL5, and MCP-1, and clear activation of the NF-kappaB signaling pathway, traced by the phosphorylation of I-kappaB-alpha and the p65 subunit.

The decisive test came when the constructs were bathed in serum drawn from children during the acute phase of Kawasaki disease, before intravenous immunoglobulin therapy, mixed at a 10 percent volume ratio into the culture medium, with serum from age-matched healthy children as the control. Within six hours, the patient serum drove the engineered arteries into a state that mirrored the disease: heightened endothelial injury and oxidative stress, intensified expression of all three adhesion molecules, a broad transcriptional inflammatory response, and robust NF-kappaB activation. The serum also triggered pyroptosis, a fiery form of programmed cell death, evidenced by upregulation of the inflammasome sensor NLRP3, the executioner protein gasdermin D, and caspase-1. This finding aligns with growing evidence that pyroptotic endothelial death contributes to the coronary artery lesions that make Kawasaki disease dangerous, and it suggests that NF-kappaB signaling and the NLRP3 inflammasome operate in a reinforcing loop rather than as separate, sequential events.

The platform then proved its worth as a drug-testing instrument. Pretreating the constructs with atorvastatin, the widely used statin, at a non-toxic concentration of 10 micromolar significantly blunted the inflammatory response to Kawasaki serum, suppressing adhesion molecule and cytokine expression and dampening NF-kappaB phosphorylation, consistent with the statin’s known anti-inflammatory, lipid-independent pleiotropic effects and with early clinical trials of atorvastatin in Kawasaki patients with coronary aneurysms. The selective NLRP3 inhibitor MCC950, also tested at 10 micromolar, likewise reduced ICAM-1 expression and inflammatory mediator transcripts, and it specifically shut down the pyroptotic machinery, lowering NLRP3, gasdermin D, caspase-1, and IL-1beta. Because intravenous immunoglobulin resistance remains a major clinical problem, the ability to distinguish these two mechanistically distinct protective strategies within a single human tissue model is exactly the kind of preclinical capability the field has lacked.

The authors are candid about the model’s current limits. The constructs were cultured under static conditions, without the fluid flow and shear stress that shape endothelial behavior in living arteries, and future versions will incorporate dynamic perfusion. The endothelial layer consists of HUVECs rather than coronary-specific endothelial cells, a pragmatic choice driven by the robust proliferation needed to form an intact barrier in a bioprinted scaffold. Even so, the achievement stands out. In a single platform, the team has combined tunable biofabrication, native-like multilayered architecture, functional barrier properties, patient-derived disease induction, and mechanistically resolved drug evaluation. For a disease that strikes young children, has no known cause, and can leave permanent cardiac damage, this bioprinted coronary artery equivalent offers a powerful new window into pathogenesis and a versatile testing ground for the therapies of tomorrow.

Subject of Research: Biomimetic 3D bioprinted coronary artery models for Kawasaki disease modeling and drug screening

Article Title: Engineering biomimetic coronary artery equivalents for Kawasaki disease modeling and drug screening

Article References: Zhang, X., Shao, C., Wang, Y., Liu, A., Rong, X., Jia, C., Yu, W., Zhang, H., Wu, R., Zhang, J., Zhang, L., Ye, F., & Chu, M. (2026). Engineering biomimetic coronary artery equivalents for Kawasaki disease modeling and drug screening. Materials Today Bio, 41, Article 103701. https://doi.org/10.1016/j.mtbio.2026.103701

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103701

Keywords: Kawasaki disease, coronary artery, bioprinting, microfluidics, GelMA, endothelial dysfunction, NF-kB, pyroptosis, NLRP3, atorvastatin, MCC950, drug screening

Cutaneous melanoma is the most lethal and aggressive cancer of the skin, arising from malignant transformation of melanocytes and marked by rapid proliferation, high metastatic potential, and notorious resistance to conventional therapies. The latest epidemiological estimates from the International Agency for Research on Cancer counted 331,722 new cases and 58,667 deaths worldwide in 2022, and even as targeted therapies and immunotherapies have transformed the landscape, low response rates and acquired resistance continue to frustrate effective management. That unmet need is precisely why the study’s authors turned their attention to two signaling systems increasingly recognized as vulnerabilities in tumors: purinergic signaling, the extracellular communication network built on adenosine triphosphate and its breakdown products, and the inflammatory axis involving interleukin-6 and the NLRP3 inflammasome.

Purinergic signaling, first proposed in 1972, operates through P1 and P2 receptors that respond to a ladder of molecules: ATP, adenosine diphosphate, adenosine monophosphate, and adenosine. Depending on which molecules dominate the extracellular space, the same pathway can drive cell proliferation or push a cell toward apoptosis. In the tumor microenvironment, the balance tilts dangerously. Extracellular adenosine, generated in abundance, acts as a potent immunosuppressant, blunting the anti-tumor immune response. The levels of these signaling molecules are controlled largely by ectonucleotidases, membrane-bound enzymes known as CD39 and CD73, along with adenosine deaminase, which breaks adenosine down into inosine. CD39 converts ATP into ADP and AMP; CD73 then hydrolyzes AMP into adenosine. Overexpression of CD73 has been documented in pancreatic adenocarcinoma, thyroid cancer, and melanoma itself, and both CD39 and CD73 have been flagged as next-generation checkpoint targets for cancer therapy.

Against that backdrop, calcitriol offered an intriguing candidate. Previous work had shown that 1-alpha,25-dihydroxyvitamin D3 induces apoptosis in melanoma cells, enhances the anticancer effects of classical chemotherapy, inhibits proliferation and migration in breast cancer models, and can modulate IL-6 expression. Yet its mechanism of action on the purinergic system in melanoma had never been systematically explored. The research team hypothesized that calcitriol exerts a potent antineoplastic effect on cutaneous melanoma by modulating the activity and expression of ectonucleotidases, thereby rewiring the extracellular nucleotide landscape in favor of tumor cell death.

To test the hypothesis, the investigators cultured two human cutaneous melanoma cell lines, A375 and SK-MEL-28, treating them with calcitriol at 1, 10, and 50 nanomolar concentrations for 24 hours. The A375 line, which displays epithelial morphology and an invasive, metastatic profile, and SK-MEL-28, a polygonal melanoma line, were subjected to a battery of assays: MTT and fluorescence microscopy viability tests, measurements of mitochondrial transmembrane potential using the TMRE dye, detection of apoptotic bodies by acridine orange staining, wound-healing migration assays, and enzymatic quantification of ATP, ADP, and AMP hydrolysis alongside adenosine deaminase activity. Gene expression of CD39, CD73, IL-6, and NLRP3 was assessed by RT-qPCR, normalized to the housekeeping gene GAPDH and analyzed with the comparative delta-delta-CT method, with one-way ANOVA and Dunnett’s post hoc test applied throughout.

The results were striking and, in one respect, unexpectedly selective. In A375 cells, calcitriol significantly reduced viability at every concentration tested, with the MTT assay yielding P values of 0.0004 at 1 nM and below 0.0001 at 10 and 50 nM. Fluorescence microscopy independently corroborated the viability loss across all doses. Crucially, the treatment also collapsed the mitochondrial transmembrane potential of A375 cells at all concentrations, with statistical significance reaching P < 0.0001, a disruption consistent with the initiation of intrinsic apoptosis. Matching that mitochondrial signature, the treated cells showed marked nuclear fragmentation: apoptotic bodies rose significantly at all three doses, while cell counts fell in a dose-dependent manner. Wound-healing assays added another dimension, revealing that calcitriol inhibited A375 migration and wound closure at every concentration tested within just 24 hours, with P < 0.0001, a finding with obvious implications for blocking metastasis.

The SK-MEL-28 line told a different story. Calcitriol produced no significant reduction in its viability and left its mitochondrial potential untouched; at 1 nM, viability even increased slightly. The researchers point to a well-documented explanation: SK-MEL-28 cells express functionally lower levels of the vitamin D receptor than several other melanoma lines, rendering them resistant to calcitriol’s antiproliferative effects at nanomolar concentrations, with prior studies noting sensitivity only at much higher doses. The contrast between the two cell lines underscores that calcitriol’s anticancer activity depends on functional vitamin D receptor signaling, a caveat that will shape which patients might ultimately benefit from a calcitriol-based adjuvant strategy.

The deepest technical insight, however, came from the purinergic analysis. Calcitriol left ATP hydrolysis unchanged but significantly decreased ADP hydrolysis at 1 and 10 nM, with a modest increase at 50 nM, and reduced AMP hydrolysis at 10 and 50 nM. Because CD39 and CD73 jointly convert ATP down the cascade to adenosine, dampened AMP breakdown means less substrate for adenosine production. Consistent with that logic, adenosine deaminase activity, which depends on adenosine availability, dropped sharply at 10 and 50 nM. At the gene level, calcitriol downregulated CD39 expression at 10 and 50 nM and exerted a strong suppressive effect on CD73 at those same concentrations, P < 0.0001. Together, these changes describe a coherent suppression of the AMP-to-adenosine axis, the very pathway tumors exploit to generate immunosuppressive adenosine in their microenvironment. By throttling adenosine generation, calcitriol may indirectly loosen the tumor’s grip on local immunity.

The inflammatory arm of the study completed the picture. Extracellular nucleotide signaling is intimately connected to inflammation, and both IL-6 and NLRP3 have dual, sometimes controversial roles in cancer, with evidence linking them to tumor progression, chemoresistance, immune cell infiltration, and poor prognosis in melanoma. Calcitriol significantly downregulated IL-6 expression at 10 nM and 50 nM, and produced an equally robust reduction in NLRP3 gene expression, with P < 0.0001 at both doses. Given that IL-6 targeting has been proposed to abrogate melanoma growth and progression, and that NLRP3 is increasingly viewed as a therapeutic target capable of reducing chemoresistance, these transcriptional effects suggest calcitriol acts on multiple fronts at once: killing tumor cells directly, impairing their migratory capacity, starving the immunosuppressive adenosine pathway, and calming the pro-tumoral inflammatory circuitry.

The authors are careful about scope. Their analysis covered gene expression rather than protein levels, and only two cell lines were examined, which they acknowledge as a limitation given the distinct metabolic profiles of A375 and SK-MEL-28. They also stress that while the nanomolar concentrations used appear practical for in vivo applications, safety testing is required, and future animal studies should monitor calcium levels to guard against hypercalcemia, the classic toxicity of active vitamin D compounds. Encouragingly, the adjuvant concept already has clinical footprints: calcitriol has been shown to enhance the effects of cisplatin and dacarbazine in melanoma cells, to combine favorably with the VEGFR inhibitor Cediranib, and, in a prospective phase Ib study, to be well tolerated in metastatic melanoma patients receiving high-dose encapsulated calcitriol alongside temozolomide, with no significant secondary side effects reported. Combined with prior evidence that calcitriol can sensitize melanoma cells to proton beam irradiation, the new purinergic mechanism adds a mechanistic rationale to an accumulating clinical case. If subsequent in vivo work confirms that calcitriol’s ectonucleotidase modulation translates into restored anti-tumor immunity, the sunshine vitamin’s most potent form could find itself written into the melanoma treatment algorithm.

Subject of Research: Antineoplastic effects of calcitriol on cutaneous melanoma cells via purinergic signaling modulation

Article Title: Calcitriol, the active form of vitamin D, induces cell death and purinergic signaling modulation in cutaneous melanoma cells

Article References: da Silva, G. B., Narzetti, R. A., Dallagnol, P., Ozelame, B. C., Manica, D., Ramos, V. H. M., Kempka, A. P., & Bagatini, M. D. (2026). Calcitriol, the active form of vitamin D, induces cell death and purinergic signaling modulation in cutaneous melanoma cells. Medical Oncology, 43(10), Article 288. https://doi.org/10.1007/s12032-026-03412-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03412-5

Keywords: calcitriol, vitamin D, cutaneous melanoma, purinergic signaling, ectonucleotidases, CD39, CD73, apoptosis, mitochondrial membrane potential, IL-6, NLRP3, adjuvant therapy

Inflammasomes are cytosolic signaling complexes assembled by pattern recognition receptors in response to a wide array of danger-associated and pathogen-associated molecular patterns. Among the best characterized is the NLRP3 inflammasome, which can be activated by an extraordinary diversity of stimuli, ranging from extracellular ATP and crystalline substances such as monosodium urate to perturbations in cellular homeostasis including mitochondrial dysfunction and ionic flux. Structural studies, notably cryo-electron microscopy analyses, have revealed that NLRP3 oligomerizes into a large ring-like platform that recruits the adaptor protein ASC through pyrin domain interactions. ASC in turn nucleates the polymerization of procaspase-1 filaments through its caspase recruitment domain, creating a branched, star-shaped assembly that has become iconic in the field of innate immunity.

The review emphasizes how this hierarchical assembly process, in which a receptor seeds adaptor polymerization which then seeds effector activation, is a recurring architectural principle across inflammasome families. DNA-sensing receptors such as AIM2 and the Pyrin family of receptors, as well as the more recently described sensors like NLRP1 and CARD8, all converge on the same downstream machinery despite recognizing fundamentally different ligands. This convergence explains how a limited set of adaptor and effector molecules can translate an enormous diversity of upstream danger signals into a uniform cellular response: the activation of inflammatory caspases, cleavage of the cytokine precursors pro-interleukin-1 beta and pro-interleukin-18, and induction of a lytic form of cell death known as pyroptosis.

Pyroptosis itself has been structurally dissected at the level of its executioner, gasdermin D. Activated inflammatory caspases cleave gasdermin D to release an N-terminal fragment that oligomerizes into membrane pores, causing osmotic lysis and the release of intracellular contents, including mature interleukin-1 beta. Recent structures of gasdermin pores have clarified how the positively charged face of the oligomer interacts with membrane lipids and how pore formation is regulated. This level of mechanistic detail has direct pharmacological implications, because small molecules that block gasdermin pore formation or inflammasome assembly could dampen pathological inflammation in conditions as varied as gout, atherosclerosis, type 2 diabetes, inflammatory bowel disease, and neurodegenerative disease, all of which have been linked to excessive inflammasome activity.

Beyond canonical inflammasomes, the review devotes substantial attention to PANoptosis, a recently articulated form of inflammatory programmed cell death that integrates features of pyroptosis, apoptosis, and necroptosis within a single, coordinated complex termed the PANoptosome. Unlike a classical inflammasome, a PANoptosome contains components from multiple cell death pathways simultaneously, including Z-DNA-binding protein 1, or ZBP1, which senses Z-form nucleic acids generated during viral infection, together with receptor-interacting protein kinases and other death-domain proteins. Structural and biochemical studies suggest that these complexes assemble through a web of homotypic and heterotypic domain interactions, creating a platform capable of activating multiple death effector machineries in parallel and amplifying inflammatory signaling to a degree that neither pathway could achieve alone.

ZBP1 has emerged as a particularly instructive example of how structural insights inform PANoptosome biology. Its two Z-nucleic acid binding domains recognize the unusual left-handed conformation of Z-DNA and Z-RNA, which accumulates in cells infected with viruses such as influenza A. Upon ligand binding, ZBP1 engages RIPK3 through RHIM domain interactions, and in certain contexts also recruits NLRP3 and ASC, thereby coupling viral sensing directly to necroptosis, pyroptosis, and cytokine release. Mutations that disrupt these interactions protect mice from lethal influenza-associated inflammation, underscoring the in vivo importance of this pathway and highlighting RHIM-mediated interactions as a potential drug target in severe viral pneumonia and other contexts of pathogenic inflammation.

One of the central themes of the review is that autoinhibition is a universal feature of innate immune sensors, reflecting the danger of accidental self-destruction if these potent inflammatory pathways are triggered spuriously. NLRP3, for example, is held in an inactive conformation by its LRR domain folding back onto the nucleotide-binding domain, a constraint released through a multi-step activation process involving NEK7 binding, deubiquitination, and translocation to the Golgi or endosomal membranes. Similar autoinhibitory mechanisms govern NLRP1, which releases its inhibitory function upon proteasomal degradation of an N-terminal regulatory segment, and pyrin, which is restrained by phosphorylation-dependent sequestration through binding to 14-3-3 proteins. Structural biology has provided atomic-level explanations for how disease-associated mutations, including those causing cryopyrin-associated periodic syndromes and familial Mediterranean fever, destabilize these autoinhibited states and drive constitutive inflammasome activation.

The therapeutic implications of this structural knowledge are considerable and span several classes of intervention. Direct inhibitors of NLRP3, such as MCC950 and its derivatives, have demonstrated efficacy in preclinical models of numerous inflammatory diseases and are progressing through clinical evaluation. Second-generation approaches include compounds that block ASC speck formation, inhibitors of inflammatory caspases, gasdermin D antagonists designed to prevent pore formation, and agents targeting upstream cytokine signaling through blockade of interleukin-1 family receptors. For PANoptosome-driven diseases, particularly severe viral infections and certain hereditary autoinflammatory syndromes, strategies that interrupt specific protein-protein interfaces, such as the RHIM-dependent interaction between ZBP1 and RIPK3, represent an emerging frontier. The review argues that structural data, by revealing precisely where and how these complexes assemble, will be indispensable for the rational design of such inhibitors.

Challenges nonetheless remain substantial. Inflammasome components are large, flexible, and often membrane-associated, complicating structural determination of full assemblies in physiologically relevant states. Much of the available structural information derives from isolated domains, truncated constructs, or oligomers assembled in vitro, and bridging the gap between these reductionist structures and the behavior of intact complexes in living cells remains a priority. Moreover, the redundancy and interconnection of inflammatory cell death pathways mean that blocking one arm may simply redirect signaling through another, arguing for combination approaches informed by a systems-level understanding of PANoptosome architecture and regulation.

Taken together, the review frames inflammasomes and PANoptosomes not as isolated curiosities of innate immunity but as a structurally unified family of molecular decision-making machines whose misregulation underlies a broad spectrum of human disease. As cryo-electron microscopy, cryogenic electron tomography, and single-molecule imaging continue to reveal these assemblies at ever higher resolution in increasingly native contexts, the prospect of precisely targeted anti-inflammatory therapeutics, capable of silencing pathological inflammation while preserving beneficial host defense, moves steadily closer to reality.

Subject of Research: Structural and mechanistic analysis of innate immune sensors that assemble inflammasomes and PANoptosomes

Article Title: Innate immune sensors of inflammasomes and PANoptosomes: structural–mechanistic insights and therapeutic implications

Article References: Upadhyay, S., Nagampalli, R., Resende, S., & Kanneganti, T.-D. (2026). Innate immune sensors of inflammasomes and PANoptosomes: structural–mechanistic insights and therapeutic implications. Cell Research. https://doi.org/10.1038/s41422-026-01287-9

Image Credits: AI Generated

DOI: 10.1038/s41422-026-01287-9

Keywords: innate immunity, inflammasome, PANoptosis, PANoptosome, NLRP3, ZBP1, ASC, caspase-1, gasdermin D, pyroptosis, structural biology, anti-inflammatory therapeutics