搜索结果：Cellular & molecular immunology

Artemisinin combination therapies are central to malaria control, but their efficacy is threatened by the emergence of resistant Plasmodium falciparum strains. While the role of Pfkelch13 mutations is well established, mutations in Pfcoronin have also been implicated in treatment failure, revealing layers of resistance complexity. Here, we define the cellular mechanism of Pfcoronin‑mediated artemisinin resistance. PfCoronin interacts with PfActin and localizes to the parasite plasma membrane, the digestive vacuole membrane, and small vesicles containing host cell material. Mutations in PfCoronin disrupt its localization and perturb PfActin homeostasis, altering the distribution of ring‑stage morphologies, including a reduced proportion of parasites adopting the cup‑shaped architecture. These changes are associated with decreased uptake of host cell contents by ring‑stage P. falciparum. Consistent with prior work on Pfkelch13 mutants, reduced hemoglobin uptake emerges as a feature of Pfcoronin‑mediated resistance. Although PfKelch13 and PfCoronin reside in distinct compartments and show no evidence of direct interaction, both influence endocytic access to hemoglobin. We propose that reduced hemoglobin uptake in ring‑stage parasites limits heme‑dependent activation of artemisinin and thus reduces its cytocidal activity. Our findings demonstrate that Pfcoronin mutations reduce endocytosis and modulate artemisinin susceptibility-highlighting how non‑essential, temporally restricted proteins can shape drug response and resistance.

Curcumin, a lipophilic polyphenol widely used in traditional medicine, is the active ingredient in turmeric (Curcuma longa L.). It has various therapeutic effects, such as antitumor potential, due to its interaction with intracellular and extracellular molecules associated with different malignancies. Ceramides are fundamental constituents of cellular membranes that maintain the stability and integrity of cells. Additionally, they have become key signaling agents that govern a spectrum of cellular functions, such as differentiation, proliferation, apoptosis, and cellular senescence. This review primarily introduces ceramides and their metabolism, summarizes their crucial roles in cancer, and categorizes and discusses the mechanisms and pathways through which curcumin could potentially exert its antitumor effects by targeting ceramides. These mechanisms include apoptosis- and autophagy-associated pathways, de novo ceramide generation, and influencing intracellular free calcium levels and acid inhibition. ceramidase, and combinational strategies using various chemical agents, ceramides, or ceramide analogs to enhance curcumin's efficacy. Finally, the review concludes with remarks and prospects for the future of curcumin's antitumor potential in the context of ceramide targeting.

Membranous nephropathy (MN) is a prototypical immune-mediated glomerular disease characterized by the formation of autoantibodies targeting podocyte antigens, deposition of subepithelial immune complexes, and activation of complement pathways leading to podocyte injury and proteinuria. The discovery of target antigens such as the M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) has substantially advanced the understanding of MN immunopathogenesis. Despite these advances, current therapeutic approaches remain limited by incomplete response rates, treatment-related toxicity, and the lack of personalized treatment strategies. Recent studies have highlighted the immunomodulatory potential of bioactive compounds derived from traditional medicinal plants. Several compounds with well-defined molecular structures including icariin, astragaloside IV, catalpol, cordycepin, and Lycium barbarum polysaccharides have demonstrated experimentally validated mechanisms affecting key molecular pathways involved in inflammation and immune regulation. These compounds modulate intracellular signaling networks such as NF-κB, PI3K-Akt signaling, NLRP3 inflammasome activation, AMPK signaling, and oxidative stress pathways, which are closely associated with immune dysregulation and podocyte injury in MN. In parallel, advances in systems biology and precision medicine are transforming the investigation of immune-mediated kidney diseases. Multi-omics technologies, biomarker discovery, artificial intelligence-assisted disease classification, and network pharmacology approaches provide integrative tools for identifying disease mechanisms and therapeutic targets. These analytical frameworks enable the systematic exploration of compound-target interactions and may facilitate the development of personalized treatment strategies for MN. This review integrates current knowledge on the immunopathogenesis of membranous nephropathy with emerging insights into bioactive compounds derived from traditional Chinese medicine (TCM) and modern systems biology approaches. By linking experimentally supported molecular mechanisms with computational and translational research strategies, this work highlights potential avenues for developing innovative immunomodulatory therapies and advancing precision medicine in immune-mediated kidney diseases.

Metastasis remains the primary cause of cancer-related mortality, driven not only by intrinsic genetic alterations but also by dynamic reprogramming of the post-metastatic microenvironment. Recent advances in multi-omics technologies-including single-cell transcriptomics, spatial profiling, methylome analysis, chromatin architecture mapping, and proteomics-have reshaped our understanding of metastatic ecosystems and revealed key regulatory nodes that coordinate tumor progression. Among these, SERPINE2 has emerged as a convergent mediator across diverse cancer types. Multi-layered evidence demonstrates that SERPINE2 integrates tumor-intrinsic signaling and microenvironmental remodeling. Mechanistically, SERPINE2 stabilizes oncogenic receptors such as EGFR by inhibiting ubiquitination-dependent degradation, sustains downstream STAT3/ERK activation, and enhances DNA damage response through ATM phosphorylation and homologous recombination repair. Concurrently, as a secreted factor, SERPINE2 promotes cancer-associated fibroblast activation, M2 macrophage polarization, extracellular matrix remodeling, and angiogenesis, collectively fostering immune suppression and metastatic persistence. These dual tumor-intrinsic and stromal functions position SERPINE2 as a molecular hub in post-metastatic adaptation. Targeting SERPINE2 may therefore represent a paradigm shift in advanced cancer therapy by simultaneously disrupting oncogenic persistence, genome maintenance, and immune exclusion. This review synthesizes multi-omics insights into SERPINE2-driven microenvironmental reprogramming and discusses emerging therapeutic strategies integrating molecular targeting and immunotherapy in metastatic cancers.

Myeloid cells are capable of releasing web-like extracellular structures composed of DNA and granular proteins, known as extracellular traps (ETs), which function to eliminate invading pathogens and modulate immune responses. Intraperitoneal vaccine administration has been demonstrated to induce ETs, but their roles in vaccine-mediated immune responses remain largely unknown. In this study, we show that a protein subunit vaccine triggers the release of ETs in the peritoneal cavity of teleost fish. Pharmacological inhibition of ET formation by 4-aminobenzoic acid hydrazide (ABAH) or enzymatic degradation of ETs by DNase I significantly reduces CD4-1+ and CD4-2+ T cell proportions in immune organs, decreases IgM+ B cell frequency in peripheral blood, and lowers antigen-specific antibody titers. Proteomic profiling of ETs generated in vivo and in vitro reveals that ET-derived proteins are enriched in molecules involved in immune regulatory pathways associated with macrophage activation, antigen presentation, and T cell proliferation and differentiation. Collectively, our findings indicate that ET-derived proteins act as core molecular scaffolds to boost vaccine-induced adaptive immune responses, offering novel insight into the bridging mechanisms between innate and adaptive immunity.

Sepsis affects an estimated 166 million individuals globally with 21.4 million annual deaths and represents a notable public health challenge. Sepsis‑induced coagulopathy (SIC) is a marked complication of sepsis, characterized by dysregulated hemostasis and microvascular thrombosis. Neutrophil extracellular traps (NETs) are pivotal mediators linking innate immunity to thrombo‑inflammation in this process. The present review systematically examined the epidemiology and pathogenesis of SIC, the molecular mechanisms of NET release (suicidal, vital, mitochondrial and non‑canonical pathways) and the mechanistic pathways by which NETs regulate SIC. NETs disrupt endothelial integrity, amplify platelet activation, propagate coagulation cascades and suppress fibrinolysis, thereby establishing a self‑amplifying cycle that accelerates progression to disseminated intravascular coagulation and multiple organ failure. Furthermore, the present review highlighted current therapeutic strategies targeting NETs, including inhibition of NET synthesis, acceleration of NET clearance and disruption of platelet‑neutrophil interactions. Elucidating the central role of NETs in SIC pathophysiology may facilitate the development of novel biomarkers and precision therapeutic interventions for this life‑threatening condition.

Tumor cells evade anti-tumor immunity by reprogramming tumor microenvironment (TME). Using multiplexed single-cell proteomics to analyze 50 TME-associated proteins across treatment-naive triple-negative breast cancer (TNBC) specimens, we discovered that cancer stem cells (CSCs) drive differentiation and expansion of regulatory T cells (Tregs) via extracellular vesicle (EV)-mediated paracrine signaling. TSPAN8, an integral membrane protein on CSC-derived EVs, interacts with CD103 (integrin αEβ7) on T cells, triggering the formation of LKB1-STRAD-MO25 complex and sequential phosphorylation of LKB1 and AMPKα. This cascade enhances FOXP3 expression, which transactivates CD103, creating a positive feedback loop that drives clonal expansion of immunosuppressive CD103+FOXP3+ Tregs and their associated niche. This EV membrane topology-based mechanism operates independently of canonical EV cargo internalization. Neutralizing EVs-TSPAN8+ with a monoclonal antibody synergized with anti-PD-1 therapy in preclinical models, suggesting a potential approach targeting both CSCs and TME immunosuppression, particularly in TNBC subpopulation with high TSPAN8+ CSCs.

Edwardsiella piscicida is an intracellular bacterial pathogen that causes intestinal injury and hemorrhagic sepsis in marine and freshwater animals. VgrG (valine-glycine repeat protein G) has been identified as a crucial virulence factor in the type VI secretion system (T6SS) of the bacterium, but its role and mechanism involved in E. piscicida-host interactions remain unclear. In this study, we found that the wild-type E. piscicida strain markedly induced host cell ferritin degradation and elevated intracellular Fe²⁺ levels, but a vgrG deletion mutant (ΔvgrG) strain failed to induce similar effects in fish cells, indicating the role of VgrG in the regulation of iron metabolism. However, in the NCOA4 (nuclear receptor coactivator 4, a selective cargo receptor that binds ferritin)-knockout fish cells, VgrG did not alter ferritin protein expression and E. piscicida-promoted intracellular Fe²⁺ levels, suggesting that VgrG caused iron storage disorders via NCOA4-dependent ferritinophagy. In support of this notion, VgrG overexpression was found to facilitate the co-localization of ferritin with autophagosomes and lysosomes, and also drove the interaction of NCOA4 with lysosomes, strengthening the involvement of this effector in mediating NCOA4-dependent ferritinophagy. Notably, in NCOA4-knockout cells, the inhibitory effect of VgrG on the intracellular growth of E. piscicida was further magnified, particularly highlighting the role of VgrG-induced ferritinophagy in augmenting bacterial intracellular survival. Moreover, zebrafish infected with the ΔvgrG strain had a much higher survival rate than those infected with the wild-type strain. In summary, our data revealed a new function of VgrG in maintaining the persistence of E. piscicida within host cells, which advanced our understanding of how intracellular pathogens target ferritinophagy to evade the host's immune surveillance. Moreover, this work also supported the potential for developing defense strategies against E. piscicida based on the VgrG-induced ferritinophagy response in fish.

Pleuroparenchymal fibroelastosis (PPFE) is a progressive interstitial lung disease (ILD) with defining histology of intra-alveolar fibrosis with septal elastosis (AFE), suggesting unique cellular disease processes. Here, we present a binational single-nucleus RNA sequencing atlas of PPFE, based on explanted lungs from 40 patients. Immunofluorescence microscopy, RNA in situ hybridization, micro-computed tomography (CT), and hierarchical phase-contrast (HiP) synchrotron CT provided spatial context. We identify PPFE-associated adventitial and elastofibrotic fibroblasts as key drivers of elastotic remodeling within an inflammatory microenvironment, maintained by immune cells forming tertiary lymphoid structures. Spatial mapping reveals an intriguing zonation of AFE, maintained by intercellular circuits between PPFE-associated cell types. Comparative analysis with idiopathic pulmonary fibrosis highlights CTHRC1+ fibrotic fibroblasts and aberrant basaloid cells as conserved profibrotic cellular machinery mediating collagen deposition across ILDs. This integrative atlas defines the cellular landscape of PPFE and dissects elastotic from fibrotic remodeling, providing a molecular rationale for niche-specific therapeutic strategies.

Microglia, the resident innate immune cells of the central nervous system, play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Microglia are now recognized as a highly dynamic and heterogeneous population whose molecular and functional states vary with spatial context, disease stage, and genetic background. Recent discoveries across multiple scales from genetics, molecular and cellular biology, to systems-level imaging and epidemiology have underscored the complex and context-dependent contributions of microglia to the AD cascade. Together, these findings highlight the need for integrative, multiscale approaches that bridge molecular, cellular, and systemic perspectives to elucidate the diverse roles of microglia and their impact on disease progression. This mini-review discusses recent advances in understanding microglial biology across these dimensions and outlines current challenges toward achieving a more unified and therapeutically oriented framework for studying microglia in AD.

Pancreatic cancer (PC)'s lethality is determined by late diagnosis and treatment resistance. The tumor microenvironment (TME), driven by cancer-associated fibroblasts (CAFs), is a crucial contributor. Within the TME, multiple cell types, including cancer cells, stromal cells, and immune cells, produce exosomes (EXOs), which are nanoscale extracellular vesicles (EVs) that mediate intercellular communication. Among these, CAF-derived EXOs (CAF-EXOs) conduct crucial interactions with cancer cells, conveying molecular cargo that promotes tumor proliferation, invasion, metastasis, metabolic reprogramming, and chemoresistance. Because CAF-EXOs provide a source of sensitive blood-based biomarkers for early detection and represent potential therapeutic targets whose disruption might overcome stromal-driven resistance, research on CAF-EXOs is crucial for addressing the fundamental shortcomings of current PC therapy. This narrative review synthesizes the critical significance of CAF-EXOs as master regulators of PC development and therapeutic resistance. We reveal how these EVs convey specialized molecular cargo, including proteins, lipids, and non-coding RNAs. By identifying CAF-EXOs as essential mediators of chemoresistance and stromal immunosuppression, we emphasize their dual potential as attractive liquid biopsy biomarkers and therapeutic targets. The study concludes with a critical examination of the translational landscape, reviewing new strategies to target exosomal biogenesis, uptake, or cargo, while also noting the enormous biological and technological challenges that must be overcome to achieve therapeutic relevance. Ultimately, altering the CAF-EXO communication axis provides a new avenue to overcome stromal-driven resistance and improve outcomes in PC.

Spinal cord injury (SCI) causes severe and persistent neurological dysfunction. Ferroptosis has been implicated in multiple neurological disorders, but its contribution to SCI and its relationship to myeloid-cell responses, inflammatory amplification and disturbed iron homeostasis remain unclear. We integrated public bulk RNA-sequencing and single-cell RNA-sequencing datasets with experiments in a rat SCI model to define ferroptosis-associated changes across the molecular, cellular and tissue levels. Differential expression, pathway enrichment, co-expression and protein-protein interaction analyses, pseudotime inference and cell-cell communication modelling were used to identify candidate molecules and relevant myeloid subpopulations, followed by qPCR, western blotting and immunofluorescence validation. Ferroptosis-associated molecular alterations in SCI showed marked temporal dynamics and remained embedded within pathological networks linked to inflammation, oxidative stress and hypoxic responses. Single-cell analysis indicated that these signals were concentrated primarily in myeloid cells, particularly the HMOX1-high M1a and M1b subclusters. Pseudotime and cell-cell communication analyses further suggested that these subpopulations progress along a continuous trajectory towards inflammation-amplifying states and may influence the local microenvironment through MIF, TGFβ, PTN and CD99 signalling. Animal experiments further showed that sustained inflammatory activation occurs in parallel with dysregulation of ferroptosis-associated molecules, accompanied by local myeloid-cell activation and enhanced HMOX1-associated stress responses. In SCI, ferroptosis-associated signals appear to be concentrated within HMOX1-associated myeloid subpopulations and may be sustained through cell-state reprogramming and intercellular signaling networks. HMOX1 emerges as a candidate hub linking disturbed iron handling, ferroptosis and myeloid inflammatory remodeling.

Colocalisation analysis integrates GWAS and molecular QTL datasets to identify candidate effector genes. Even with a wide range of molecular QTLs, 40% or more of GWAS loci remain unexplained, leaving a "colocalisation gap". We systematically characterised two large-scale eQTL colocalisation studies, to describe the determinants of this gap and ultimately inform the selection and design of eQTL studies to close the gap. We analyse over 1.3 million colocalisation tests from Open Targets Genetics (OTG) and perform and analyse colocalisations from 14 immune-mediated disease (IMD) GWAS and 12 diverse immune cell eQTL studies, selected to cover a range of cellular granularities and sample sizes. We find that 50% of GWAS peaks in OTG and 34% in IMDs colocalised and were more likely to colocalise if they were located nearer to genes and had a more common lead variant. Colocalisation was also more likely to occur in disease relevant tissues. The lowest granularity immune cell eQTL studies had the largest sample sizes, the greatest eQTL discovery and produced the largest number of colocalisations, particularly for lower-frequency variants. However, while higher resolution eQTL studies detected fewer eQTLs, each of those eQTLs was more likely to colocalise with a GWAS peak, emphasising the importance of cell specific eQTLs. Indeed, over 50% of colocalisations were found in only one cell type. Overall, our results suggest that a diverse set of cells in different contexts, and large, high granularity studies will be needed to identify remaining colocalisations. In addition, we observed that 47% of GWAS peaks colocalised with multiple genes in OTG and 37% in IMDs. Through simulations, sensitivity analyses, and integration of enhancer-promoter capture data we find that multiple colocalisations likely represent coregulation. While disentangling causality from horizontal pleiotropy will ultimately require experimental perturbation, triangulation using different sources of observational data is likely to be necessary for gene prioritisation.

Super-enhancer-associated long non-coding RNAs (lncRNAs) have been shown to play key roles in the occurrence and development of malignant tumors, including esophageal squamous cell carcinoma (ESCC), yet their precise molecular mechanisms remain elusive. ChIP-Seq, dual-luciferase reporter assays, HiChIP-Seq, and ChIP-qPCR were performed to investigate the transcriptional regulation mechanism of MIR205HG. The functions and downstream signal transduction mechanisms of MIR205HG in ESCC were explored by a series of in vitro and in vivo assays. Furthermore, comprehensive bioinformatics methods were used to analyze its correlation with ESCC patient survival. Here, we identified and characterized MIR205HG, a lncRNA driven by super-enhancer, as a crucial oncogene in ESCC. MIR205HG was up-regulated in SCCs and its high expression correlated with poor clinical outcomes. Both TP63 and KLF5, two important master transcription factors in ESCC, could simultaneously occupy the super-enhancer region at the MIR205HG locus to promote its transcription and overexpression. MIR205HG is essential for ESCC proliferation, migration, invasion, and the growth of xenograft tumors in vitro and in vivo. Mechanistically, MIR205HG directly bound PTBP3 and acted as a molecular scaffold to promote HIF-1α translation, leading to enhanced cellular glycolysis via up-regulating the expression of HK2 and LDHA. Moreover, survival and pseudotime analyses of ESCC scRNA-seq data revealed a significant positive correlation between MIR205HG/PTBP3 signaling and the stemness and malignancy of ESCC cells. Finally, we showed that specifically targeting MIR205HG-SE using a CRISPR interference method resulted in potent suppressive effects on ESCC malignant phenotypes. We identified a pivotal oncogenic super-enhancer-driven lncRNA, MIR205HG, which interacts with PTBP3 to promote glycolysis in ESCC. It may serve as a promising prognostic biomarker and therapeutic target for patients.

The gut-lung axis links early-life microbial programming to long-term respiratory health, offering a pivotal framework for understanding childhood asthma pathogenesis. This review synthesizes current evidence on how disruptions in microbial-immune crosstalk during critical developmental windows shape asthma susceptibility. Perinatal determinants-including maternal diet, delivery mode, antibiotic exposure, and breastfeeding-establish gut microbial communities that educate the developing immune system. Distinguishing itself from recent reviews, this review offers three novel contributions: (i) an integrated multi-omics framework linking early-life microbial maturation trajectories to specific asthma endotypes; (ii) a systematic synthesis of the molecular mechanisms by which microbial metabolites-including short-chain fatty acids, tryptophan derivatives, and bile acids-orchestrate gut-lung immune crosstalk; and (iii) a clinically actionable precision medicine algorithm that translates multi-omics profiling into personalized risk prediction, endotype-driven therapy selection, and targeted preventive strategies. Dysbiosis, characterized by delayed microbial maturation and depletion of short-chain fatty acid-producing taxa, compromises epithelial barrier integrity and skews immune homeostasis toward pro-allergic type-2 responses. Microbial metabolites, particularly short-chain fatty acids (acetate, propionate, butyrate) and tryptophan derivatives (indole-3-lactic acid, indole-3-propionic acid), serve as key molecular mediators that regulate regulatory T cells differentiation, reinforce mucosal barriers, and modulate distal airway inflammation. Microbial signatures correlate with specific asthma endotypes, offering opportunities for patient stratification. We critically evaluate emerging microbiome-targeted interventions-including strain-specific probiotics, prebiotics, postbiotics, and fecal microbiota transplantation-highlighting both therapeutic promise and the need for rigorous, well-powered clinical trials. Integrating multi-omics microbial profiling with host genetics and clinical phenotyping holds potential for microbiome-informed precision medicine, enabling personalized risk prediction, endotype-driven therapy selection, and novel preventive strategies targeting the gut-lung axis from the earliest stages of life.

Gene regulatory microRNA (miRNA) have emerged as promising biomarkers and therapeutic targets in autoimmunity pathology. This study examines circulatory miRNA as cellular biomarkers that can distinguish rheumatoid arthritis (RA) from psoriatic arthritis (PsA) to evaluate the potential implications for disease pathogenesis. RA (n&#x2009;=&#x2009;48) and PsA (n&#x2009;=&#x2009;50) patients and healthy controls (HC) (n&#x2009;=&#x2009;20) were recruited and serums obtained. Multiplex analysis of serum miRNAs was performed using the FirePlex miRNA Immunology-V2 panel (FirePlex Bioworks Inc.). DNA intelligent analysis (DIANA)-mirPath and STRING software were used to predict pathways targeted by the dysregulated miRNAs. 7 miRNAs; miR-126-3p, miR-29b-3p, miR-22-3p, miR-223-3p, miR-320a, let-7e-5p, and let-7g-5p were significantly elevated in RA serum compared with PsA (all p< 0.05), in addition to HC (all p< 0.05), with high sensitivity and specificity as determined by receiver-operating characteristic curve analysis. PCA and biplot analysis demonstrated differential miRNA clustering between both disease states with a dominant skew towards 3 specific miRNA in RA vs PsA; miR-29b-3p, miR-22-3p, and miR-223-3p. DIANA analysis and STRING visualisation of this miRNA signature identified downstream target pathways including PI3K-Akt and FoxO signalling, all importantly associated with aspects of RA pathogenesis including angiogenesis, invasion, and cell death. This study identified three key miRNAs demonstrating differential expression levels between RA and PsA, which potentially govern downstream inflammatory pathways regulating distinct disease mechanisms. Therefore, circulating miRNAs may be valuable as non-invasive diagnostic biomarkers that can distinguish RA from PsA and may additionally assist in elucidating differential disease pathogenesis.

Long non-coding RNAs (lncRNAs) are critical context-dependent regulators of viral infection, functioning as double-edged swords in host defense and viral pathogenesis. Accumulating evidence demonstrates that host lncRNAs exert antiviral effects by modulating innate immune responses, regulating host cell survival/apoptosis, or directly targeting viral genomes. Conversely, viruses exploit lncRNA functions to evade immune surveillance, suppress antiviral signaling, and promote viral replication. This review synthesizes current literature to elucidate the molecular mechanisms governing the functional duality of lncRNAs and their dynamic switching between proviral and antiviral roles during infection. Understanding the precise control of this functional switch is crucial for translating lncRNA biology into novel therapeutic strategies. The functional duality of lncRNAs reflects their deep integration into cellular networks. Harnessing their potential demands mechanistic understanding, precision diagnostics, and dynamically responsive interventions. Key lncRNA-pathway interactions offer promising targets for rationally designed RNA-based antivirals against chronic and drug-resistant viruses.

Protein inhibitor of activated STAT 1 (PIAS1) functions as a SUMO E3 ligase, regulating cardiovascular diseases by promoting the SUMOylation of target proteins; however, its role in abdominal aortic aneurysm (AAA) remains unclear. Currently, molecular targeted therapies for AAA are still very limited. This study aimed to clarify whether PIAS1 regulates the stability of the PPAR&#x3b3; protein through SUMOylation to elucidate its molecular mechanisms in AAA formation and to evaluate its potential as a novel therapeutic target. AAA rat models were established via the infusion of porcine pancreatic elastase, and an in vitro cell model was constructed by treating human umbilical vein endothelial cells (HUVECs) with Ang II. Flow cytometry, ELISA, H&E staining, and EVG staining were used to assess cell and abdominal aortic tissue damage, while RT-qPCR and Western blotting were used to detect the expression of relevant genes and proteins. This study revealed that PIAS1 is expressed at low levels in AAA. The overexpression of PIAS1 effectively inhibited Ang II-induced lipid accumulation and inflammatory responses in HUVECs and AAA rats, alleviated pathological damage and apoptosis in the abdominal aorta, and alleviated the progression of AAA. With respect to the regulatory mechanism, the SUMOylation and expression levels of PPAR&#x3b3; are downregulated in AAA. PIAS1 primarily stabilizes PPAR&#x3b3; expression by promoting its SUMOylation, thereby inhibiting lipid accumulation and inflammatory responses. Further studies revealed that SENP3 is highly expressed in AAA and that PIAS1 can downregulate SENP3 levels, thereby attenuating its deSUMOylation effect on PPAR&#x3b3; and ultimately promoting the SUMOylation and expression of PPAR&#x3b3;. PIAS1 alleviates the progression of AAA by inhibiting SENP3 expression, thereby promoting PPAR&#x3b3; SUMOylation and protein expression, which in turn reduces lipid accumulation and inflammatory responses.

Psoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation and inflammation, largely driven by the cytokines IL-22 and interferon (IFN)-&#x3b3;. These cytokines activate the signal transducer and activator of transcription (STAT) 3 and STAT1 molecular pathways, leading to abnormal proliferation, impaired differentiation, and increased production of inflammatory mediators in keratinocytes. While the IL-22/STAT3 pathway primarily promotes de-differentiation in keratinocytes, IFN-&#x3b3;/STAT1-3 signaling induces pronounced inflammation, despite exerting antiproliferative effects on these cells. Recent research has highlighted the role of serine/glycine metabolism in the pathogenesis of psoriasis, by supporting T cell and keratinocyte proliferation. Furthermore, pharmacological inhibition of serine catabolism through targeting serine hydroxymethyltranferase (SHMT)1/2 enzymes reduced the infiltration of inflammatory cells in the skin of the imiquimod-induced mouse model of psoriasis. This study investigates the role of serine catabolism in psoriasis, focusing on its influence on keratinocyte proliferation and inflammation. We examined how pharmacological inhibition of SHMT1/2, mediated by a folate-competitive cell-permeable inhibitor Serine Hydroxymethyltransferase INhibitor 1 (SHIN1), affects keratinocyte proliferation and inflammatory signaling pathways in response to psoriasis-associated cytokines IL-22 and IFN-&#x3b3;, using both in vitro and ex vivo models of the disease. We found that SHIN1 reduced keratinocyte proliferation, particularly under IL-22 stimulation, and restored differentiation in ex vivo psoriasis skin explants by reversing the effects of IL-22. SHIN1 also inhibited IFN-&#x3b3;-induced expression of pro-inflammatory genes (e.g., CXCL10, CXCL9, CCL5, CCL2, IL-6) and reduced STAT3 activation, with only modest effects on STAT1 and extracellular signal-regulated kinase 1/2 activation. In psoriasis explants, SHIN1 decreased the expression of Ki67, Keratin 16, and pro-inflammatory cytokines including IL-17A, IL-22, and IFN-&#x3b3;. These findings support the therapeutic potential of SHIN1 as a metabolism-targeted agent for psoriasis and other cytokine-mediated skin disorders, providing a rationale for further exploration of novel treatment strategies.