International immunopharmacology最新文献

{"title":"Sinigrin ameliorates cardiac inflammation and fibrosis by partly modulating the Wnt/GSK-3β/β-catenin signaling: Insights from in vitro and in vivo models","authors":"Anjali Veeram ,&nbsp;Ramakrishna Sistla ,&nbsp;Sai Balaji Andugulapati","doi":"10.1016/j.intimp.2025.115593","DOIUrl":"10.1016/j.intimp.2025.115593","url":null,"abstract":"<div><div>Myocardial fibrosis is characterized by the thickening of the heart interstitium due to the deposition of extracellular matrix proteins. Sinigrin (SNG) has been shown to possess antioxidant and anti-inflammatory activities. The present investigation sought to explore the anti-fibrotic effects of SNG against cardiac inflammation and fibrosis through relevant models. An isoproterenol hydrochloride (ISH)-induced differentiation model using HCMEC, HCF, HCM, and H9C2 cells was employed <em>in vitro</em>, while an ISH-mediated cardiac inflammation/fibrosis model was used <em>in vivo</em> to evaluate the therapeutic effect of SNG through molecular biology, ECG, and histological analyses. Gene/protein expression analyses showed that ISH stimulation notably elevated the levels of key inflammatory markers (IL-1β, TNF-α, IL-6, and cofilin) and fibrotic markers (FN-1, α-SMA, collagen types I, III, and TIMP-1) in the ISH control group. However, SNG (25, 50, and 100 μg/mL) treatment markedly attenuated these elevations in cardiac endothelial cells, fibroblasts, and myocytes. In a rat model, ISH administration (5 mg/kg) markedly elevated injury markers and immune cell levels (ALT, AST, neutrophils, and lymphocytes) in blood samples, along with increased levels of oxidative stress indicators, inflammatory and fibrotic markers in cardiac tissues. Histopathological analysis revealed significant pathological alterations, including inflammatory cell infiltration, fibroblast proliferation, collagen deposition, and cardiomyocyte disorganization. However, SNG treatment (7.5, 15, and 30 mg/kg) effectively attenuated these ISH-induced changes in a dose-dependent manner. The findings of this study demonstrate that sinigrin exhibits potent anti-inflammatory/anti-fibrotic properties by partially modulating the Wnt/GSK-3β/β-catenin signaling pathway. These findings highlight sinigrin's potential as a therapeutic candidate for cardiac inflammation and fibrosis, supporting future translational research.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115593"},"PeriodicalIF":4.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"A novel vaccine strategy against brucellosis using Brucella abortus multi-epitope OMPs vaccine based on Lactococcus lactis live bacterial vectors\" [Int. Immunopharmacol. 134 (2024) 112204].","authors":"Tohid Piri-Gharaghie, Ghazal Ghajari, Golnoosh Rezaeizadeh, Mohaned Adil, Mohammed H Mahdi","doi":"10.1016/j.intimp.2025.115559","DOIUrl":"https://doi.org/10.1016/j.intimp.2025.115559","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":" ","pages":"115559"},"PeriodicalIF":4.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Geniposide alleviates rheumatoid arthritis by inhibiting pyroptosis by regulating the miR-223-3p/NLRP3 Axis","authors":"Xuan-ting Fan ,&nbsp;Chao Li ,&nbsp;Ping Dong ,&nbsp;Hua Hao ,&nbsp;Hua Lian ,&nbsp;Hao Wu ,&nbsp;Li-mei Ao ,&nbsp;Chun-jie Ma","doi":"10.1016/j.intimp.2025.115598","DOIUrl":"10.1016/j.intimp.2025.115598","url":null,"abstract":"<div><div>Geniposide (GE) has anti-inflammatory effects; however, its mechanism of action in RA is unclear. This study examined the protective properties of GE against RA and explored its possible molecular mechanisms. The effectiveness of treatment of GE was measured using a using a type II collagen-induced arthritis (CIA) model. Paw swelling, arthritis score, and histopathological alterations in the ankle joint, serum levels of autoantibodies inflammatory cytokines, and Western blotting (WB), were used to determine GE's efficacy in CIA rats. In vitro experiments were performed using flow cytometry, TUNEL assays, and WB to detect expression levels of NLRP3, GSDMD-N, Cleaved-Caspase-1. Direct binding of miR-2233p to NLRP3 was experimentally validated using dual-luciferase reporter systems. Subsequently, RT-qPCR and WB were used to measure protein levels. Our results demonstrated that GE significantly alleviated the symptoms of arthritis in CIA rats, with reduced paw swelling, lower arthritis scores, and attenuated histopathological joint damage. GE treatment suppressed serum levels of anti-CII autoantibodies, TNF-α, IL-1β, and IL-18, while downregulating NLRP3, Caspase-1, and GSDMD expression in the ankle joint. These findings were corroborated in LPS/ATP induction of RAW264.7 macrophages, where GE similarly attenuated pyroptosis markers. Dual-luciferase reporter assays confirmed that NLRP3 was a key target point of miR-223-3p. Furthermore, Western blot and RT-qPCR test results confirmed miR-223-3p as the key target of GE suppression of NLRP3 inflammasome activation and pyroptosis. Collectively, our findings indicate that GE Alleviates RA by inhibiting pyroptosis through the regulation of the miR-2233p/NLRP3 axis, highlighting its potential as a valid therapeutic agent for RA.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115598"},"PeriodicalIF":4.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variability of respiratory syncytial virus and its impact on monoclonal antibody binding sites: a national cross-sectional study during the 2023–2024 season","authors":"Antonio Piralla ,&nbsp;Greta Romano ,&nbsp;Carla Acciarri ,&nbsp;Stefano Menzo ,&nbsp;Sara Uceda Renteria ,&nbsp;Annapaola Callegaro ,&nbsp;Cristina Galli ,&nbsp;Laura Pellegrinelli ,&nbsp;Alessandra Pierangeli ,&nbsp;Matteo Fracella ,&nbsp;Federica Novazzi ,&nbsp;Nicasio Mancini ,&nbsp;Cristina Russo ,&nbsp;Stefania Ranno ,&nbsp;Elisa Vian ,&nbsp;Donna Damian ,&nbsp;Elisabetta Pagani ,&nbsp;Elisa Masi ,&nbsp;Elena Pomari ,&nbsp;Concetta Castilletti ,&nbsp;Elena Pariani","doi":"10.1016/j.intimp.2025.115591","DOIUrl":"10.1016/j.intimp.2025.115591","url":null,"abstract":"<div><h3>Background</h3><div>Respiratory syncytial virus is a primary cause of acute lower respiratory tract infections globally. As preventive tools such as vaccines and monoclonal antibodies begin to enter clinical use, baseline genomic data are critical to evaluate their future impact and detect potential resistance-related mutations. The working group on respiratory viral infections (GLIViRe) conducted this multicenter study to characterize the genetic profile of RSV circulating in Italy during the 2023–2024 season, immediately prior to the introduction of immunoprophylactic interventions. The study focused on identifying mutations in the F protein at mAb binding sites for palivizumab, nirsevimab, RSM01, TNM-001, and clesrovimab.</div></div><div><h3>Methods</h3><div>A total of 350 respiratory samples positive for RSV collected from patients with influenza-like illness (ILI) or acute respiratory infection (ARI), during the 2023–2024 season from 15 Italian laboratories were selected for sequence analysis. The F gene sequencing was performed on 287 RSV-A and 63 RSV-B samples using Sanger or next-generation sequencing. Phylogenetic analysis was conducted using IQ-TREE, with the integration of global data via NextStrain. Key mutations were mapped onto the F protein structure using ChimeraX and Protein Data Bank models. Shannon entropy was used to assess amino acid variability.</div></div><div><h3>Results</h3><div>RSV-A samples predominantly belonged to the emerging A.D, A.D.1, and A.D.3 clades, while RSV-B samples mainly clustered in the B·D lineage. Key substitutions were detected at antigenic site ∅, particularly at the nirsevimab and RSM01 interfaces. No changes occurred at the palivizumab/TNM-001 site II. All mutations of interest were exposed to the F protein surface.</div></div><div><h3>Conclusions</h3><div>This study provides a critical genomic snapshot of RSV in Italy prior to the introduction of vaccines and mAbs. Continuous surveillance is essential for monitoring viral evolution and supporting the long-term effectiveness of future immunization strategies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115591"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Green synthesis of copper oxide nanoparticles from Calotropis gigantea of antimicrobial, antidiabetic, and toxicity evaluation in zebrafish","authors":"Azhagu Madhavan Sivalingam","doi":"10.1016/j.intimp.2025.115581","DOIUrl":"10.1016/j.intimp.2025.115581","url":null,"abstract":"<div><div><em>Calotropis gigantea</em> (giant milkweed or crown flower), a traditional medicinal plant used to treat various ailments, contains toxic compounds that require careful handling. In this study, copper oxide nanoparticles (CuO NPs) were synthesized using an eco-friendly green method with <em>C. gigantea</em> leaf ethanol extract ofsynthesized and characterized copper oxide nanoparticles (CG-CuO NPs) using UV–Vis spectrophotometry, FT-IR, XRD, SEM, and EDX. The study evaluated the in vitro bioactivity of the CG-CuO NPs leaf extract focusing on their antidiabetic, anti-inflammatory, cytotoxic, and antimicrobial properties. The Phytochemical screening of secondary metabolites such as flavonoids, tannins, steroids, saponins, polyphenols which act as efficient bio-reductants and capping agents, leading to smaller, more stable CuO nanoparticles with superior bioactivity. <strong>Characterization and confirmation of CG-CuO NPs synthesis</strong> by UV–Visible spectroscopy confirmed nanoparticle formation, showing a characteristic absorbance peak at 437 nm. <strong>Stabilization analysis</strong> of FTIR analysis identified hydroxyl, amine, carboxyl, and aromatic functional groups involved in nanoparticle stabilization, with prominent absorption bands at 1072 cm⁻¹ and 530 cm⁻¹. <strong>Morphology and size</strong> of SEM revealed predominantly spherical nanoparticles with smooth surfaces and uniform dispersion. The TEM images showed that the particle sizes ranged from 35 to 85 nm, following a narrow quasi-Gaussian size distribution. <strong>The crystallinity and Composition</strong> of XRD analysis confirmed the crystalline monoclinic phase of the CuO NPs (matching JCPDS No. 48–1548). Elemental analysis indicated that copper oxide was the major component (75.37 wt%), with trace amounts of carbon, sodium, and oxygen. <strong>Toxicity analysis</strong> of zebrafish embryotoxicity assays showed concentration- and time-dependent developmental toxicity, including deformities and mortality. Decreasing LC₅₀ and EC₅₀ values between 24- and 120-h post-fertilization indicated increasing toxicity over time. <strong>Biological Activities</strong> of the biogenic CuO NPs exhibited strong biological effects, including potent α-glucosidase inhibition (IC₅₀ = 22 μg/mL). The significant anti-inflammatory activity (IC₅₀ = 109 μg/mL) exceeded that of the chemically synthesized counterparts. The CG-CuO NPs exhibited selective anticancer potential, with an IC₅₀ of 31.5 μg/mL against MCF-7 breast cancer cells compared to 124.8 μg/mL in non-cancerous HaCaT keratinocytes, demonstrating preferential cytotoxicity toward cancer cells. <em>C. gigantea</em>-synthesized CuO nanoparticles demonstrate promising antidiabetic, anti-inflammatory, and selective anticancer properties of green synthesis and biocompatibility supporting potential biomedical applications.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115581"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Siglec14-TLR2 axis mediates anti-HIV-1 immunity in macrophages","authors":"Minjuan Shi ,&nbsp;Beibei Lu ,&nbsp;Wudi Wei ,&nbsp;Shanshan Chen ,&nbsp;Jie Liu ,&nbsp;Xi Hu ,&nbsp;Rongfeng Chen ,&nbsp;Zongxiang Yuan ,&nbsp;Jinming Su ,&nbsp;Xiu Chen ,&nbsp;Qiao Tang ,&nbsp;Yuting Wu ,&nbsp;Li Ye ,&nbsp;Hao Liang ,&nbsp;Junjun Jiang","doi":"10.1016/j.intimp.2025.115595","DOIUrl":"10.1016/j.intimp.2025.115595","url":null,"abstract":"<div><div>HIV-exposed seronegative (HESN) individuals exhibit natural resistance to HIV-1 infection, providing a unique model to identify host factors that confer protection against the virus. Building upon our previous transcriptomic studies identifying Siglec14 as a key correlate of HIV-1 resistance in HESN individuals, we investigated its functional role in HIV-1 pathogenesis. We found that HIV-1 infection upregulates Siglec14 in macrophages, where it suppresses viral replication through potent antiviral activity. Mechanistically, Siglec14 directly interacts with HIV-1 Nef protein and subsequently engages TLR2, triggering phosphorylation and activation of NF-κB p65 and IRF3. This dual signaling cascade initiates robust antiviral responses via (1) NF-κB-mediated production of proinflammatory chemokines (CXCLs), and (2) IRF3-dependent induction of type I interferons (e.g., IFN-β) and interferon-stimulated genes (ISGs). Our results establish Siglec14 as a critical innate immune sensor that orchestrates antiviral defenses through TLR2-mediated signaling, highlighting its potential as a therapeutic target for HIV immunotherapy and vaccine development.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115595"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protective role of TRIM16 in rheumatoid arthritis: mechanisms of modulating ferroptosis","authors":"Nannan Xu ,&nbsp;Wenyi Fu ,&nbsp;Jiake Wu ,&nbsp;Shuai Zhao ,&nbsp;Chunyang Tian","doi":"10.1016/j.intimp.2025.115573","DOIUrl":"10.1016/j.intimp.2025.115573","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, and ferroptosis has been associated with its pathogenesis. TRIM16 belongs to the TRIM protein family and possesses various biological function. However, the role of TRIM16 in RA has not been reported. Our results showed that TRIM16 was upregulated in collagen-induced arthritis (CIA) mice, and TRIM16 overexpression alleviated joint inflammation. Notably, the level of 4-HNE was decreased in CIA mice, whereas TRIM16 overexpression restored it. The expression of GPX4 and SLC7A11 was upregulated in CIA mice, whereas TRIM16 overexpression significantly suppressed their levels, suggesting that TRIM16 promotes ferroptosis. We then detected TRIM16 expression in TNF-α-induced fibroblast-like synoviocytes (FLS), and found that TNF-α stimulation reduced TRIM16 expression. Overexpression of TRIM16 increased the lipid ROS, Fe²⁺ levels, and LDH activity, while reducing GSH-PX and GSH activities. Moreover, TNF-α treatment increased GPX4 and SLC7A11 expression but decreased ACSL4 levels, and TRIM16 overexpression reversed these effects. TRIM16 knockdown reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Furthermore, Fer-1 treatment reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Mechanistically, TRIM16 directly binds to Snai1, promoted its K48-linked ubiquitination, and specifically ubiquitinates Snai1 at the K146 site. Overexpression of Snai1 decreased the lipid ROS levels and increased the GSH content. Our study identifies TRIM16 as a promoter of ferroptosis in TNF-α-induced FLS by enhancing Snai1 ubiquitination and degradation. In summary, our study presented that TRIM16 plays a protective role in RA.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115573"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to \"How microRNAs affect the PD-L1 and its synthetic pathway in cancer\" [Int. Immunopharmacol. 84 (2020) 106594].","authors":"Gholamreza Rezaei Danbaran, Saeed Aslani, Nadia Sharafkandi, Maryam Hemmatzadeh, Ramin Hosseinzadeh, Gholamreza Azizi, Farhad Jadidi Niaragh, Farhad Babaie, Hamed Mohammadi","doi":"10.1016/j.intimp.2025.115574","DOIUrl":"10.1016/j.intimp.2025.115574","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":" ","pages":"115574"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aloperine exerts anti-tumor effect and activates the tumor cell-intrinsic STING pathway in gallbladder cancer","authors":"Yushun Chang ,&nbsp;Jie Lin ,&nbsp;Bo Yang ,&nbsp;Yuxuan Shen ,&nbsp;Weijun Zhao ,&nbsp;Hao Shen ,&nbsp;Quan Yang ,&nbsp;Haowen Lu ,&nbsp;Xiujun Cai ,&nbsp;Yifan Wang ,&nbsp;Wen Hua","doi":"10.1016/j.intimp.2025.115590","DOIUrl":"10.1016/j.intimp.2025.115590","url":null,"abstract":"<div><h3>Background</h3><div>Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, exhibits anticancer activity in several malignancies, but its efficacy and mechanisms in gallbladder cancer (GBC) remain undefined.</div></div><div><h3>Methods</h3><div>Human GBC cell lines (GBCs) were treated with ALO and assessed for viability, colony formation, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation and apoptosis. Autophagic flux and related signaling were evaluated by western blotting and immunofluorescence. In vivo antitumor activity was determined in a nude mouse xenograft model.</div></div><div><h3>Results</h3><div>ALO markedly inhibited the proliferation ability of GBCs and disrupted autophagosome–lysosome fusion, leading to reactive oxygen species (ROS) accumulation and apoptosis. Furthermore, ALO induced DNA damage and nuclear release of double-stranded DNA (dsDNA) to cytoplasm, leading to cyclic-GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-mediated interferon (IFN) pathway activation and enhancing natural killer cells (NK cells) activation in vitro. In vivo, ALO reduced subcutaneous GBCs xenograft volume and weight and, along with increased cleaved caspase-3 and BAX expression in tumor tissues, confirming tumor cell apoptosis.</div></div><div><h3>Conclusions</h3><div>These findings indicate that ALO may serve as a novel therapeutic candidate for gallbladder cancer by inhibiting autophagic flux to induce ROS-mediated apoptosis while activating the cGAS–STING–IFN pathway to enhance antitumor immunity.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115590"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Six1 promotes alveolar epithelium senescence in pulmonary fibrosis through regulating Tp53","authors":"Yan Fan,&nbsp;Zhen Tian,&nbsp;Hongyan Zheng,&nbsp;Rongman Xu,&nbsp;Boyu Li,&nbsp;Shanshan Wang,&nbsp;Zhenli Huang,&nbsp;Meijia Wang,&nbsp;Dan Ding,&nbsp;Jianping Zhao,&nbsp;Jungang Xie","doi":"10.1016/j.intimp.2025.115554","DOIUrl":"10.1016/j.intimp.2025.115554","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a deadly respiratory condition distinguished by gradual fibrotic restructuring and diminishing pulmonary capacity, with cellular senescence serving as a critical factor in its pathogenesis. This study investigated the function of Sine oculis homeobox homologue 1 (Six1), a transcription factor, in pulmonary fibrosis (PF) and assessed its therapeutic potential as a target. The expression of Six1 was reduced in type II alveolar epithelial cells (AECII) in both patients with IPF and mouse models of PF induced by bleomycin (BLM). Conditional overexpression of Six1 in AECII exacerbated fibrosis severity, as confirmed by histological analysis and impaired lung function. RNA sequencing indicated the involvement of Six1 in pathways related to immune response, inflammation, and cellular senescence. Mechanistic studies revealed that Six1 promotes cellular senescence in AECII by directly upregulating Tp53 transcription, a process mitigated by treatment with PFN-α, a Tp53 inhibitor. Inhibition of Six1 using the specific repressor NCGC00378430 (NCG) attenuated fibrotic changes and improved pulmonary function in both Six1-overexpressing and wild-type mice. These findings suggest that Six1 is a contributor to the progression of IPF by regulating AECII senescence, emphasizing the therapeutic potential of targeting Six1 to alleviate PF. This study underscores the necessity of exploring Six1 inhibitors further as promising candidates for treating IPF.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115554"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}