Atopic dermatitis (AD) is a highly heterogeneous chronic inflammatory skin disease, and the exact role and mechanisms of interleukin (IL)-19 in AD remain unclear. This study integrated serum samples from AD patients, transcriptomic data from clinical AD lesions, AD-like mouse models with exogenous IL-19 supplementation or IL-19 gene knockout, and in vitro cellular models to investigate its mechanism of action. Serum IL-19 levels correlated with disease severity after adjustment for clinical covariates and type 2 cytokines in this cohort. In an MC903-induced AD-like mouse model, exogenous IL-19 supplementation exacerbated the dermatitis phenotype, whereas IL-19 gene knockout alleviated it. Mechanistically, keratinocytes constituted the primary source of IL-19 within AD lesions, with house dust mites inducing its upregulation in these cells in vitro. IL-19 acted through the STAT6/STAT3 signaling pathway to suppress loricrin and keratin-10 expression, which may result in epidermal barrier impairment. Simultaneously, it upregulated thymic stromal lymphopoietin and IL-33, potentially facilitating the type 2 inflammatory cascade in AD. Furthermore, IL-19 may additively exacerbate inflammatory responses with IL-13 and IL-4. Collectively, these findings support a role for IL-19 as a pro-inflammatory mediator in AD, suggesting that IL-19 contributes to both epidermal barrier dysfunction and type 2 immune dysregulation in this disease.
Sepsis-associated encephalopathy (SAE) is a sepsis-induced neurological disorder characterized by neuroinflammatory responses and cognitive impairment; however, the molecular mechanisms underlying microglial inflammatory activation in SAE remain incompletely understood. A caecal ligation and puncture (CLP)-induced sepsis model and lipopolysaccharide (LPS)-exposed primary microglia were used to evaluate the contribution of serum amyloid A1 (SAA1) to SAE. Multiomics profiling combined with functional manipulation, coimmunoprecipitation, glutathione S-transferase (GST) pull-down assays, and in silico virtual screening were applied to investigate the mechanistic basis of SAA1-mediated responses and evaluate the effects of Forsythoside I (FI). CLP induced significant cognitive impairment, hippocampal injury, neuroinflammation, and microglial pyroptosis. Multiomics analyses identified SAA1 as a markedly upregulated inflammatory mediator that is predominantly localized in microglia. SAA1 knockdown alleviated cognitive deficits, reduced neuroinflammation, and suppressed NLRP3 inflammasome activation and pyroptosis. Mechanistically, SAA1 physically interacted with TLR4 and promoted downstream NF-κB activation, leading to increased NLRP3 inflammasome activation and pyroptosis. Rescue experiments further demonstrated that the proinflammatory effects of SAA1 were dependent on TLR4 signalling. In addition, computational analyses predicted a potential interaction between FI and SAA1, while FI treatment attenuated SAE-associated neuroinflammatory injury and was accompanied by reduced SAA1 expression and suppression of downstream TLR4/NF-κB signalling and NLRP3 inflammasome activation. These results indicate that SAA1 contributes to microglial inflammatory activation and pyroptosis in SAE through TLR4/NF-κB-dependent NLRP3 inflammasome signalling. FI exerts neuroprotective and anti-inflammatory effects accompanied by modulation of SAA1-associated inflammatory signalling; however, whether SAA1 represents a direct molecular target of FI remains to be established. Collectively, pharmacological modulation of SAA1-associated inflammatory signalling may represent a potential therapeutic strategy for SAE.
Atherosclerosis is a chronic inflammatory disease marked by the accumulation of lipid-laden plaques and immune cell infiltration within the arterial wall. Platelets and their derived microvesicles (PMVs) are recognized as critical modulators of T cell activation via direct contact and miRNA transfer, including miR-142-3p, a regulator of immune function and survival. The aim of this study was to investigate the immunomodulatory effects of platelets and MVs from healthy mice on splenic T cells in a murine model of advanced atherosclerosis. Platelets, MVs, and splenic T cells were isolated from two experimental groups: (1) C57BL/6J mice on standard chow for 12 weeks as the healthy control group (C) and (2) ApoE−/− mice fed a high-fat, high-cholesterol diet for 12 weeks, as the advanced atherosclerotic group (HFHC). T cells were stimulated in vitro and co-incubated with platelets or MVs from control mice for 3 days. Flow cytometry and qRT-PCR were used to assess activation markers, miR-142-3p levels, and gene expression. HFHC mice showed increased platelet counts, elevated P-selectin levels, and a fourfold increase in circulating MVs, along with enhanced platelet-T cell aggregation. Concomitantly, T cells from HFHC mice exhibited reduced activation (CD8⁺CD69⁺ and CD4⁺CD154⁺ subsets) and augmented IL-17 production, compared to control. At the molecular level, miR-142-3p was consistently reduced in plasma, platelets, and MVs from HFHC mice relative to controls, suggesting systemic depletion of this regulatory miRNA with disease progression. Consistent with this, co-incubation with control-derived platelets and MVs significantly elevated intracellular miR-142-3p in control T cells-an effect entirely absent in HFHC T cells. Finally, MV treatment differentially reprogrammed gene expression depending on the T cell origin: in control T cells, MVs upregulated Cxcl4, integrin αV, Bax, and Bcl2, whereas in HFHC T cells, they reduced integrin αV and increased TGF-β1 expression, pointing to divergent immunomodulatory programs. Our findings suggest that miR-142-3p may contribute to PMV-mediated modulation of T cell responses, but these effects are impaired under atherogenic conditions, highlighting a disrupted platelet-T cell communication axis in atherosclerosis.
Systemic lupus erythematosus (SLE) is characterized by dysregulated immune responses. Paeoniflorin (PF), a highly purified monoterpene glycoside derived from Paeonia lactiflora, exhibits immunomodulatory activity, but its mechanisms in SLE remain unclear. This study investigated whether PF ameliorates SLE by modulating the gut microbiota–lipid metabolite axis and restoring Th17/Treg immune balance. Network pharmacology was applied to predict PF-related targets and pathways in SLE. MRL/lpr mice were treated with PF, and disease severity was assessed by clinical manifestations, autoantibody levels, renal function, and histopathology. Intestinal barrier integrity and motility were evaluated in vivo. Th17 and Treg cell populations in intestinal and peripheral immune tissues were analyzed by flow cytometry. Gut microbiota composition was profiled using 16S rRNA gene sequencing, and untargeted LC–MS/MS–based metabolomics of intestinal contents was performed to identify differential metabolites and enriched metabolic pathways. PF treatment significantly alleviated lupus-like manifestations in MRL/lpr mice, including reduced splenomegaly and lymphadenopathy, decreased serum anti-dsDNA, ANA, total IgG, and IL-17 levels, and improved renal function and histopathological injury. PF restored Th17/Treg balance by suppressing IL-17–producing CD4⁺ T cells and promoting Foxp3⁺ Treg cells across intestinal and peripheral immune compartments. PF also improved intestinal barrier integrity and reshaped gut microbial composition by reducing inflammation-associated taxa and enriching beneficial bacteria. Metabolomic analysis demonstrated that PF markedly downregulated glycerophospholipid metabolism, particularly reducing lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC), which have been reported to promote RORγt activity and Th17 differentiation. Correlation analyses linked microbial alterations with lipid metabolite changes and Th17/Treg-associated immune parameters. Paeoniflorin alleviates SLE by regulating a gut microbiota–lipid metabolite–immune axis, suppressing pro-Th17 lysophospholipid metabolism and restoring Th17/Treg immune homeostasis.
Despite global control efforts, tuberculosis remains a major public health challenge. In the lungs, dendritic cells (DCs) are among the first cells infected by members of the Mycobacterium tuberculosis complex (MTC), where they link innate and adaptive immunity. MTC exploits host lipid metabolism, particularly triacylglycerol (TAG) stored in lipid droplets (LDs), to support intracellular survival and persistence. While the role of LDs has been extensively investigated in macrophages, their function in DCs remains poorly understood. Here, we investigated the role of TAG synthesis in DC activation and bacterial burden during mycobacterial infection, with a focus on diacylglycerol acyltransferase-1 (DGAT1) and the eicosanoid prostaglandin (PG)E2. Bone marrow-derived DCs (BMDC)s from C57BL/6 mice infected with M. bovis BCG exhibited increased LD formation, TAG and cholesterol ester accumulation, and upregulation of the transcription of lipid-related and proinflammatory genes. Pharmacological inhibition of DGAT1 with A922500 reduced bacterial burden, LD accumulation, and mRNA expression of Nos2, Il1b, and Il6, as well as the secretion of IL-1β, IL-6, IL-10, IL-23, and TNF-α. However, DGAT1 inhibition did not alter the expression of DC activation markers. Interestingly, PGE2 secretion was also reduced by inhibition of DGAT-1. Given PGE2’s established role in TB immunity and T cell differentiation, exogenous PGE2 was added to infected DCs, leading to an increase in bacterial load, cytokine release, and LD accumulation, reversing the effects of DGAT1 inhibition. These findings indicate that TAG synthesis via DGAT1 and PGE2 signaling are critical modulators of LD formation and the inflammatory response in DCs during mycobacterial infection.
Periodontitis is a chronic infectious disease initiated by periodontal pathogens, in which immune responses contribute to both pathogen clearance and tissue destruction. The metabolic and structural integrity of the gingival epithelium is critical to its role as the primary barrier maintaining periodontal immune homeostasis against bacterial invasion. However, under pathological conditions, it remains unclear how immune-epithelial cell interactions influence immune defense by affecting normal iron metabolism in epithelial cells, thereby altering susceptibility to periodontitis. In our study, integrated biochemical, histopathological, and single-cell transcriptomic analyses of gingival tissues revealed a close association between subepithelial macrophages with oxidative stress dysregulation and ferroptotic gingival epithelial cells. We further introduced echinatin and demonstrated that it alleviates oxidative stress and pro-inflammatory activation in macrophages while reversing macrophage-induced ferroptosis in gingival epithelial cells. Consistently, in vivo experiments showed that echinatin attenuated periodontal destruction, suppressed epithelial ferroptosis, and restored epithelial metabolic balance. Subsequent transcriptomic profiling of murine gingival tissues combined with network pharmacology identified the IL-6–GP130–STAT3 axis as a potential target mediating the anti-ferroptotic effects of echinatin. Pharmacological inhibition studies further demonstrated that IL-6 plays a critical role in macrophage-induced epithelial ferroptosis. Mechanistically, echinatin was shown to directly target the IL-6 receptor GP130, thereby inhibiting STAT3 signaling and suppressing ferroptosis. Collectively, these findings provide the first evidence that immune–epithelial crosstalk contributes to periodontitis progression by disrupting epithelial metabolic homeostasis and impairing epithelial barrier function. Additionally, our study identifies echinatin as a potential therapeutic agent capable of ameliorating periodontitis through modulation of immune–epithelial interactions.
Previous studies from our group confirmed the chondroprotective effects of the PPARγ agonist pioglitazone. In the present study, we aimed to elucidate the mechanism by which PPARγ activation protects against osteoarthritis (OA), with a particular focus on the regulation of Connexin 43 (Cx43). OA models were established in mice and rats through exercise and intra-articular AGE-BSA injections. Cx43-knockout mice were used for genetic validation. Primary human and rat chondrocytes were treated with AGEs in vitro. Mechanistic investigations were performed using RNA-sequencing, co-immunoprecipitation, ubiquitination assays, cycloheximide chase assays, and functional tests. Cx43 expression was markedly upregulated in OA chondrocytes and inversely correlated with PPARγ levels. The PPARγ agonist pioglitazone alleviated OA and was accompanied by elevated PPARγ and reduced Cx43 protein levels without altering Cx43 mRNA levels. Genetic ablation of Cx43 attenuated OA severity, and under pioglitazone treatment, Cx43-KO mice did not exhibit additional protection compared with WT mice, whereas Cx43 overexpression reversed the drug’s protection. Mechanistically, PPARγ activation promoted Cx43 degradation via a post-translational pathway. Integrated RNA-sequencing and IP-MS analyses identified SUMO2 and the E3 ligase adaptor Fbxo6 as key mediators of this process. Specifically, PPARγ upregulated SUMO2, which mediated Cx43 SUMOylation, facilitating its recognition by Fbxo6. This led to Cx43 ubiquitination and proteasomal degradation. Mutation of either Cx43 SUMOylation site (K109 or K133) or the disruption of the Fbxo6 SUMO-interacting motif (SIM) abolished this regulation. Functionally, activation of the SUMO2/Fbxo6 axis protected chondrocytes from AGEs-induced dysfunction. PPARγ activation triggers SUMO2-mediated Cx43 SUMOylation, thereby promoting Fbxo6-dependent ubiquitination and degradation of Cx43. This novel PPARγ-SUMO2-Fbxo6 axis is essential for chondroprotection, and provides new mechanistic insight and potential therapeutic targets for OA treatment. Clinical trial number: not applicable.
Atherosclerosis and myocardial infarction remain the predominant contributors to mortality despite advances in interventional cardiology. Chronic inflammatory responses mediated by macrophages serve as a critical determinant of the pathogenesis of cardiovascular diseases. This review systematically dissects the immunometabolic and signaling networks underlying macrophage reprogramming, with a focus on key cardiovascular diseases. We assess the characteristics of M1 macrophages, which involve aerobic glycolysis, activation of the pentose phosphate pathway, and disruption of the tricarboxylic acid cycle, compared to M2 macrophages that rely on oxidative phosphorylation and fatty acid oxidation. Integrated signaling pathways dynamically regulate these metabolic programmes—centred on TLR/NF-κB-mediated inflammatory priming, JAK/STAT-dependent transcriptional polarization, and PI3K/Akt/mTOR-AMPK-PPARγ metabolic checkpoints, which interpret microenvironmental signals to control macrophage polarization. Within atherosclerotic lesions, we demonstrate that M1-dominant macrophage populations exacerbate plaque inflammation and compromise structural integrity, whereas M2 macrophages augment inflammatory resolution and tissue restoration. Following myocardial infarction, the timely therapeutic reprogramming from M1 to M2 phenotype is essential for efficiently attenuating adverse cardiac remodeling and improving cardiac function. Targeting metabolic enzymes and signaling pathways offers a promising strategy for reprogramming macrophages and mitigating cardiovascular diseases. Addresses species-specific differences in human vs murine immunometabolism. Emphasizes the context‑dependent roles of signaling pathways in macrophage polarization. Discusses the spatiotemporal dynamics of macrophage subsets in CVDs. Proposes precision macrophage reprogramming strategies with therapeutic timing.
Chronic inflammation underlies autoimmune, metabolic, cardiovascular, and neurodegenerative disorders and remains difficult to manage because current anti-inflammatory therapies often have systemic adverse effects and variable clinical efficacy. This review synthesizes evidence on microbiome-associated metabolites relevant to inflammation, including short-chain fatty acids, microbial indole derivatives, secondary bile acids, polyamines, trimethylamine N-oxide, and selected host-microbe co-metabolites. These compounds regulate host immunity through G-protein-coupled receptors, nuclear receptors, epigenetic mechanisms, inflammasome regulation, and major inflammatory signaling pathways such as NF-kappaB, MAPK, and JAK-STAT. The translational potential of direct metabolite administration, prodrug design, microbiome engineering, dietary modulation, and targeted delivery systems is discussed alongside key limitations, including low bioavailability, context-dependent activity, interindividual microbiome variation, incomplete pharmacokinetic data, and the limited number of well-controlled human trials. Overall, microbiome-associated metabolites represent promising but still evolving therapeutic candidates; their clinical use requires stronger causal evidence, standardized formulations, safety evaluation, and disease-specific validation. Microbiome-associated metabolites, including short-chain fatty acids, microbial indole derivatives, secondary bile acids, and polyamines, contribute to epithelial homeostasis and regulate immune signaling through pathways such as NF-kappaB, MAPK, JAK-STAT, inflammasome activation, GPCR signaling, and epigenetic remodeling. Therapeutic strategies such as metabolite supplementation, prodrug design, microbiome engineering, and nano-delivery systems may enable targeted anti-inflammatory effects, but their clinical application remains dependent on stronger human evidence and standardized delivery approaches.
Metabolic dysfunction- associated steatohepatitis (MASH) represents the progressive form of metabolic dysfunction- associated steatotic liver disease (MASLD). Tubastatin A (TA), a selective HDAC6 inhibitor, possesses anti-inflammatory and epigenetic modulatory properties, but its therapeutic potential in MASH remains unexplored. The MASH model was developed using a high-fat, high-fructose (HFFrD) diet in C57BL/6J animals for 12 weeks. After model development, HFFrD animals were randomised into three groups: MASH, MASH + TA (10 mg/kg), and MASH + TA (20 mg/kg). Furthermore, control animals were randomised into two groups: control and TA_Per Se (20 mg/kg), and TA was administered via the i.p. route for 6 weeks. Further, we have performed network pharmacology analysis to identify hub genes. TA treatment significantly improved morphometric parameters and attenuated metabolic abnormalities and liver injury markers. Additionally, TA treatment significantly reduced MASH-associated oxidative stress by restoring levels of malondialdehyde, nitrite, glutathione, and superoxide dismutase. The histopathological assessment demonstrated TA's hepatoprotective effects as evidenced by significant reductions in steatosis, hepatocellular ballooning, inflammatory infiltrates, and collagen deposition. Moreover, histopathological analysis of colon tissue revealed that TA treatment improved intestinal architecture and mucosal integrity. Mechanistically, TA downregulated HDAC6 and restored α-tubulin expression, suppressed lipogenic and gluconeogenic genes, restored FGF-21 expression, and reduced inflammatory and fibrotic gene expression. At the protein level, TA modulates the expression of AMPK, NF-κB, and Nrf2, thereby attenuating MASH. Further, the network pharmacology analysis also supported the role of TA in modulating epigenetic mechanisms in MASH by regulating HDACs. Overall, TA attenuates MASH by targeting multiple interconnected pathways, including lipogenesis, metabolic stress, oxidative damage, inflammation, and fibrosis, via HDAC6 inhibition, thereby modulating AMPK and FGF21 signalling, supporting its potential as a therapeutic candidate for MASH with fibrosis.
Myocardial ischemia-reperfusion injury (MIRI) drives oxidative DNA damage in cardiomyocytes and triggers sterile inflammation, leading to leukocyte infiltration and microvascular dysfunction. Preservation of endothelial barrier integrity is crucial for limiting inflammatory cell trafficking and mitigating MIRI. In this work, FOXF1 was identified as a significantly upregulated gene in MIRI mouse myocardial tissues by mRNA-sequencing. In vivo, AAV9-mediated FOXF1 overexpression markedly improved cardiac function, reduced infarct size, and attenuated cardiomyocyte apoptosis and leukocyte infiltration after MIRI. Mechanistically, FOXF1 overexpression attenuated DNA damage in MIRI mice and oxygen-glucose deprivation/reoxygenation (OGD/R) treated HL-1 cells, which was associated with stabilization of the Fanconi anemia (FA) core complex. Concurrently, overexpression of FOXF1 upregulated VE-cadherin in cardiac endothelial cells (ECs) and inhibited the levels of Ly6G and pro-inflammatory adhesion molecules. The protective effect of FOXF1 upregulation on the endothelial barrier integrity was also confirmed in vitro, as evidenced by reduced hyperpermeability and leukocyte transmigration under OGD/R conditions. Further mRNA sequencing, combined with chromatin immunoprecipitation and dual-luciferase reporter assays, revealed that FOXF1 directly binds to the promoter region of CDH2 (Cadherin-2) and transcriptionally activates its expression in ECs. Overexpression of CDH2 reduced hyperpermeability and leukocyte transmigration of ECs under OGD/R conditions. Suppression of CDH2 reversed the resistance effects of FOXF1 overexpression on endothelial permeability and leukocyte transmigration. Collectively, our findings suggest that FOXF1 confers cardioprotection against MIRI through two distinct but complementary mechanisms: attenuating DNA damage in cardiomyocytes and transcriptionally upregulating CDH2 to preserve endothelial barrier integrity, thereby inhibiting leukocyte infiltration.
Noncanonical inflammasome activation mediated by caspase-11 drives macrophage pyroptosis and inflammatory amplification in sepsis, but endogenous restraining mechanisms remain incompletely understood. Here, we investigated the role of Nur77 (NR4A1) in cytosolic LPS-induced pyroptotic signaling using RAW264.7 macrophages and an early cecal ligation and puncture (CLP) sepsis model. LPS priming followed by cytosolic LPS stimulation increased Nur77 expression, caspase-11 cleavage, GSDMD processing, lactate dehydrogenase release, and IL-1β release. Nur77 knockdown aggravated membrane damage, increased GSDMD-N generation and pyroptosis-associated cells, and enhanced IL-1β and IL-18 release. Conversely, Nur77 overexpression attenuated caspase-11/GSDMD-associated readouts and reduced pyroptosis-associated injury. This stimulation condition also increased pannexin-1 and P2 × 7 expression, extracellular ATP release, and Yo-PRO-1 uptake; and these changes were amplified by Nur77 deficiency and blunted by Nur77 overexpression. Wedelolactone treatment attenuated caspase-11-associated readouts and was accompanied by reduced pannexin-1/P2 × 7-related responses. In vivo, pharmacological modulation of Nur77 in the early CLP model was associated with corresponding changes in systemic IL-1β/IL-18 levels, lung, liver, and kidney injury, and caspase-11/GSDMD-associated readouts. Collectively, these findings support a model in which Nur77 acts as an endogenous negative modulator of caspase-11/GSDMD-associated pyroptotic signaling and inflammatory amplification during early sepsis.
Sinomenine (SIN) has been established to exert neuroprotective effects in ischemic stroke (IS), yet its specific molecular targets and detailed mechanisms remain incompletely understood. This study identified Fermt2 as a critical target through which SIN exerted its neuroprotective effects in IS. In a rat model of cerebral ischemia-reperfusion injury, overexpression of Fermt2 improved neurological deficits, reduced cerebral infarct volume by nearly one-third, and significantly decreased neuronal apoptosis in the ischemic penumbra. In vitro and in vivo experiments demonstrated that upregulation of Fermt2 promoted a shift in microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby suppressing pro-inflammatory cytokines and restoring anti-inflammatory factors. Mechanistic investigations revealed that Fermt2 functioned by inhibiting the RhoA/ROCK/NF-κB signaling pathway. Crucially, knockdown of Fermt2 reversed the beneficial effects of SIN in IS rats. In conclusion, Fermt2 is a master regulator of microglia-dependent neuroinflammation and a promising therapeutic target for IS.
Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic, erosive synovitis. While significant progress and breakthroughs have been made in disease diagnosis through basic research and clinical practice, approximately 30
Extracellular high mobility group box 1 (HMGB1) serves as a key damage-associated molecular pattern that drives the pathological process of inflammatory liver injury; however, its role in liver fibrosis and the underlying mechanisms need to be elucidated. To investigate the proinflammatory and profibrotic roles of extracellular HMGB1, we used an adenovirus-mediated system to measure HMGB1 secretion in mice. We subsequently constructed two recombinant proteins, PfTrx-HMGB117(95 − 111) and HBcΔ-HMGB134(150 − 183), targeting the interactions of HMGB1 with its receptors, namely, toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), respectively. Mice were immunized with the two recombinant proteins to assess neutralizing antibody induction and the protective effects of the HMGB1 vaccines against carbon tetrachloride (CCl4)-induced liver fibrosis. Our results revealed the nucleocytoplasmic translocation of HMGB1 in the livers of both humans and mice with fibrosis. Extracellular HMGB1 induced liver inflammation and fibrogenesis in mice. Immunization with the two HMGB1 vaccines resulted in the production of high levels of anti-HMGB1 neutralizing antibodies, which inhibited the activation of hepatic stellate cells (LX-2) and the production of proinflammatory and profibrotic factors in RAW 264.7 cells. Furthermore, vaccination with these compounds significantly protected against CCl4-induced liver injury, inflammation, and fibrosis in mice. These findings demonstrate that extracellular HMGB1, by binding to TLR4 or RAGE, is pivotal in driving liver inflammation and fibrosis. Vaccination against HMGB1 through disruption of interaction with TLR4 or RAGE represents a promising therapeutic strategy for hepatic fibrosis.
Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by dysregulation of the joint immune microenvironment, in which macrophages play a pivotal role. This study aimed to elucidate the mechanisms by which macrophage mitochondrial function regulates immune phenotypes to drive OA progression. Through integrated analysis of single-cell RNA sequencing and bulk transcriptome data from the GEO database, we identified JUN and ATG7 as key macrophage genes associated with mitochondrial autophagy and immune regulation. A diagnostic model based on LASSO regression (RiskScore = JUN × (-0.165) + ATG7 × 0.151) demonstrated high accuracy (AUC = 0.99 in training and 0.93 in validation sets). Mechanistically, JUN and ATG7 form an “inflammation-metabolism” regulatory axis: JUN promotes pro-inflammatory M1 polarization and enriches pathways like TNF and IL-17, while ATG7 supports anti-inflammatory M2 polarization and metabolic pathways such as PI3K-Akt. Cellular and animal experiments confirmed that modulating JUN/ATG7 expression influences macrophage polarization and ameliorates cartilage degeneration. This study reveals a inflammation-metabolism regulatory axis centered on JUN/ATG7 in OA macrophages, offering new insights for molecular subtyping, early diagnosis, and targeted therapeutic strategies.
The development of fatty liver has been associated with hepatic metabolic derangements. Genistein has been reported to be a treatment option for Non-alcoholic fatty liver disease (NAFLD). In this study, we evaluated the effect of genistein on hepatic steatosis through the silent mating type information regulation 2 homolog − 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/peroxisome proliferator-activated receptor α (PPARα) and Nrf2 signaling pathways in mice fed a high-fat diet (HFD). After 10 weeks of HFD feeding, the mice were randomly divided into the HFD and genistein (0.2
Calcific aortic valve disease (CAVD) involves fibro-calcific remodeling, in which osteogenic differentiation of valvular interstitial cells (VICs) is a key process. Although inflammation is implicated, uncertainties persist regarding how defined pro-inflammatory pathways are transcriptionally coupled to the VIC osteogenic program at the cell-intrinsic level. We implemented an interleukin-17 (IL-17) pathway-guided transcriptomic strategy in a pure human VIC osteogenic differentiation model. RNA sequencing identified osteogenesis-associated differentially expressed genes and IL-17-related inflammatory signatures. Functional enrichment and multilayer network analyses were applied to prioritize candidate regulatory nodes, followed by in vitro validation. An IL-17-associated transcriptional program was activated during VIC osteogenic differentiation and was enriched for stress-activated and MAPK-related inflammatory pathways. Network-based analyses consistently identified the AP-1 transcription factor JUN as a central regulatory node within this IL-17-linked signature. Experimentally, JUN expression increased during VIC osteogenic differentiation, and JUN silencing attenuated calcification. IL-17 A rapidly increased the p-c-JUN/JUN ratio, and prolonged treatment upregulated JUN and IL-17RA in a concentration-dependent manner. Exogenous IL-17 A stimulation enhanced calcification-related phenotypes in VICs, which were partially reversed by JUN knockdown. In a chronic kidney disease-induced mouse CAVD model, JNK inhibition with SP600125 reduced valve calcification and leaflet thickness. IL-17-associated inflammatory signaling is engaged during VIC osteogenic differentiation and may promote calcification, partially through a JUN-dependent mechanism. These findings provide insight into how inflammatory programs interface with osteogenic transcription and offer a framework for dissecting inflammation-driven calcification in CAVD.
