International Journal of Immunopathology and Pharmacology最新文献

{"title":"Diagnostic preparedness for Inborn Errors of Immunity among primary care and non-immunology healthcare professionals in Kazakhstan: A cross-sectional questionnaire based study.","authors":"Gulzada Abdushukurova, Ainash Oshibayeva, Kumissay Babayeva, Banu Kadyrbayeva, Zhulduz Mirzabekova, Alken Auyelova","doi":"10.1177/03946320261471029","DOIUrl":"10.1177/03946320261471029","url":null,"abstract":"<p><p>Introduction/ObjectivesInborn Errors of Immunity (IEIs) are rare disorders in which delayed diagnosis leads to significant morbidity and mortality. Early recognition depends largely on primary care and non-immunology healthcare professionals; however, data on IEI awareness in Central Asia are limited. This study assessed the awareness of IEI among healthcare professionals in Kazakhstan and identified the association with higher diagnostic preparedness.MethodsA nationwide cross-sectional study was conducted from January to March 2025 using an online questionnaire distributed across multiple regions of Kazakhstan. Physicians and nurses affiliated with the immunology department were excluded. The survey was adapted from the Jeffrey Modell Foundation framework and demonstrated high internal consistency (KR-20 = 0.94). Descriptive analyses and multivariable logistic regression were performed.ResultsA total of 239 healthcare professionals participated (88.7% female; mean age, 38.3 ± 10.2 years). While 72.4% reported undergraduate exposure to immunology, only 30.5% received postgraduate or workplace-based training related to IEI. Overall, 40.6% of the respondents were familiar with the \"10 warning signs\" of IEI. Prior workplace-based training was independently associated with higher awareness (adjusted OR 12.6, 95% CI 6.43-24.65).ConclusionsAwareness of IEI among non-immunology professionals in Kazakhstan remains limited. Targeted workplace-based education and continuing medical education (CME) programs may improve early recognition and referral rates.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261471029"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148654798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptosis enhancement in MCF-7 cells: Synergistic effects of doxorubicin and the novel sulfonamide Zm-093.","authors":"Shabnam Pedarpour, Sevda Zarei, Hossein Ghafouri","doi":"10.1177/03946320261422036","DOIUrl":"10.1177/03946320261422036","url":null,"abstract":"<p><strong>Introduction: </strong>Breast cancer (BC) is a major global health issue. Combination therapies using chemical compounds have shown potential benefits, including reduced toxicity, slowed cancer cell growth, and improved treatment outcomes, compared to single-drug treatments.</p><p><strong>Objectives: </strong>This study investigates the synergistic effects of doxorubicin (DOX) and Zm-093, a novel sulfonamide derivative with unique properties that offer potential advantages over existing sulfonamide compounds, including enhanced solubility and improved bioavailability, on apoptosis induction in BC cell lines.</p><p><strong>Methods: </strong>Zm-093 was synthesized, and its structure was confirmed through Fourier-transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy. Cell viability was assessed using the MTT assay, while the combination index (CI) was calculated with Compusyn software to evaluate the synergistic interaction between DOX and Zm-093 in MCF-7 cells. The apoptotic effects of these compounds were further analyzed using western blotting, flow cytometry, and TUNEL assays.</p><p><strong>Results: </strong>Notably, the combined treatment of DOX and Zm-093 at concentrations of 0.36 µM and 14.5 µM resulted in a 57% reduction in Bcl-2 expression compared to the control group. In contrast, expressions of pro-apoptotic proteins Bax and tBid, as well as caspase-3, increased significantly by 2.4, 3.3, and 5.7 times, respectively. Flow cytometry and TUNEL assay results indicated that the combination therapy significantly enhanced early apoptosis while minimizing necrosis.</p><p><strong>Conclusion: </strong>These findings confirm that DOX and Zm-093 exhibit synergistic effects on apoptotic pathways in MCF-7 cells, highlighting the potential of Zm-093 as a novel therapeutic agent with improved efficacy and reduced toxicity compared to existing sulfonamide compounds.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261422036"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13100426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral keratinocyte-mediated inflammation and epithelial disruption: A narrative review on IRF6 signaling and oral carcinogenic risk.","authors":"Yuliana Andrea Osorio-Osorno, Monica Tatiana Parada-Sanchez","doi":"10.1177/03946320251411432","DOIUrl":"10.1177/03946320251411432","url":null,"abstract":"<p><p>The oral epithelium is a dynamic interface between host and environment, where keratinocytes not only serve as structural components but also actively modulate immune responses. Emerging research identifies IRF6 as a pivotal regulator of epithelial differentiation and immune signaling within chronic inflammatory contexts. This narrative review explores the role of IRF6 and its downstream effects in oral keratinocytes, particularly in relation to Toll-like receptor (TLR) activation, CCL5-mediated inflammation, hypoxic signaling, and the epithelial-mesenchymal transition (EMT). It proposes a mechanistic framework for understanding the progression from chronic inflammation to epithelial disruption and malignant transformation in oral mucosal disorders. Modulation of IRF6 signaling represents a promising therapeutic target for restoring epithelial integrity and halting disease progression in chronic inflammatory oral diseases. This model lays groundwork for future research integrating molecular biomarkers and immune modulation strategies in oral pathology.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320251411432"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12775295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated administration of cannabidiol decreases splenic lymphocyte subset numbers in rats.","authors":"Tara H Turkki, Maciej M Jankowski, Wojciech Glac, Piotr Badtke, Viviane M Saito, Artur H Swiergiel, Bogna M Ignatowska-Jankowska","doi":"10.1177/03946320251411441","DOIUrl":"10.1177/03946320251411441","url":null,"abstract":"<p><strong>Objective: </strong>Cannabidiol (CBD) administration (5 mg/kg) in healthy rats has been shown to significantly decrease lymphocyte subset numbers in peripheral blood without involvement of natural killer cells. The aim was to evaluate whether lymphocyte numbers also decrease in the spleen.</p><p><strong>Introduction: </strong>CBD, the major non-psychotropic compound of Cannabis sp., is an effective treatment for inflammatory and autoimmune diseases with various anti-tumor effects, but the mechanisms of its long-term actions in vivo remain unclear.</p><p><strong>Methods: </strong>To examine the effects of CBD on lymphocyte subsets in the spleen and NK cellular cytotoxicity (NKCC), adult male Wistar rats (<i>n</i> = 63) were administered intraperitoneal injections of CBD (2.5 or 5 mg/kg/day) for 14 consecutive days, and lymphocyte counts were obtained using flow cytometry. NKCC in the peripheral blood and spleen was quantified using a Chromium-51 release assay. Furthermore, the effect was similar to a decrease in lymphocytes caused by treatment with the selective receptor antagonist AM630 (1 mg/kg).</p><p><strong>Results: </strong>The results indicate that repeated administration of CBD at a dose of 5 mg/kg/day decreased splenic lymphocyte numbers, involving T and non-T/NK CD45RA+ lymphocytes but not NK cells. The effects of CB₂ receptor antagonist were not significant, but it had a significant interaction with CBD. No changes in NKCC were observed following CBD administration.</p><p><strong>Conclusion: </strong>These results reveal that in healthy rats, CBD produces similar lymphopenic effects in the spleen as it does in peripheral blood without affecting NK cell counts or cytotoxicity.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320251411441"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12783575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes of isoniazid preventive therapy in pregnant women living with HIV: A systematic review and meta-analysis.","authors":"Sufyan Shahid, Hasiba Karimi, Bilal Ahmad, Usama Hafeez, Biruk Demisse Ayalew, Abdullah","doi":"10.1177/03946320261427990","DOIUrl":"10.1177/03946320261427990","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the safety and effectiveness of isoniazid preventive therapy (IPT) in pregnant women living with HIV (WLWH) through a systematic review and meta-analysis.</p><p><strong>Introduction: </strong>Isoniazid preventive therapy (IPT) is recommended for preventive treatment of tuberculosis in high risk groups. However, evidence on its role in pregnant WLWH remains scarce.</p><p><strong>Methods: </strong>We performed a systematic review and meta-analysis to pool randomized controlled trials (RCTs) as well as non-randomized studies (NRS) where IPT was administered to pregnant WLWH (PROSPERO ID: CRD42024618836). PubMed, Embase, and Cochrane Central databases were searched for relevant articles, until November 15, 2024. Statistical analysis was performed using R Software v4.4.1 and a random-effects model was applied to pool risk ratios (RRs) along with 95% confidence intervals.</p><p><strong>Results: </strong>Five studies with a total of 45,402 patients (mean age = 30 years) were included. The risk of maternal mortality was significantly decreased in pregnant WLWH exposed to IPT compared with the control group (RR 0.42; 95% CI 0.20-0.92; <i>p</i> = 0.03). However, the risks of other outcomes including composite adverse pregnancy outcome (RR 0.90; 95% CI 0.56-1.43; <i>p</i> = 0.66), prematurity (RR 0.86; 95% CI 0.46-1.60; <i>p</i> = 0.63), low birthweight (RR 0.99; 95% CI 0.69-1.42; <i>p</i> = 0.95), very low birthweight (RR 1.28; 95% CI 0.39-4.23; <i>p</i> = 0.55), congenital anomalies (RR 1.48; 95% CI 0.59-3.75; <i>p</i> = 0.41), and hepatotoxicity (RR 0.99; 95% CI 0.71-1.37; <i>p</i> = 0.93) were comparable between the two groups.</p><p><strong>Conclusion: </strong>IPT in pregnant WLWH significantly reduces maternal mortality without increasing adverse pregnancy outcomes. These findings support the continued use of IPT during pregnancy, with careful monitoring for hepatotoxicity, and highlight its potential role as an important maternal health intervention in high TB/HIV burden regions.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261427990"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12988268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147460720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary epithelioid angiosarcoma of thyroid: A case report and review of literature.","authors":"Xiaoxia He, Letian Yang, Guorong Yang, Weitao Zhang, Li Ma, Haiyun Wang, Fenghua Su, Dunhui Ma, Yankun Li, Li Jiao","doi":"10.1177/03946320261440424","DOIUrl":"10.1177/03946320261440424","url":null,"abstract":"<p><p>Epithelioid angiosarcoma (EA) is a malignant tumor of endothelium origin that most commonly arises in the deep soft tissues of extremities but may occasionally be primary in skin, adrenal gland, and bone. A 72-year-old male presented with a painless enlargement of his thyroid for more than 10 days before hospitalization. A walnut-sized mass in the right thyroid was found simultaneously by palpation and Color Doppler Ultrasound. After a total thyroidectomy was performed, a mass with a size of 4.5 cm × 3.5 cm was found at the lower pole of the right thyroid gland. Histologically, the tumor was diffusely distributed in a sheet-like pattern, with tumor cells being epithelioid. There was extensive coagulative necrosis while no components of papillary carcinoma, follicular carcinoma and insular poorly differentiated carcinoma were noticed. CD31 and vimentin were positive for immunostaining. The diagnosis of primary epithelioid angiosarcoma of right thyroid was then given to the patient. Eleven months after the operation, the patient died from brain metastasis. It is suggested that primary epithelioid angiosarcoma of thyroid, as an extremely rare tumor, have no characteristic clinical manifestations, laboratory and imaging examinations, and the diagnosis mainly depend on its unique clinical pathological features. Although extensive surgical resection is the preferred treatment, the prognosis is still very poor.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261440424"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147635043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing tumor heterogeneity and FLOT/FOLFOX-induced alterations in cancer stem cells and cancer immune checkpoint molecules using patient-derived tumor organoids.","authors":"Chih-Cheng Cheng, Bor-Chyuan Su, Wei-Yu Chen, Hsin-Hsien Yu","doi":"10.1177/03946320261474427","DOIUrl":"10.1177/03946320261474427","url":null,"abstract":"<p><p>BackgroundGastric cancer is a deadly disease with poor prognosis and unfavorable therapeutic outcomes. It is known that a major cause of treatment failure for gastric cancer is related to tumor heterogeneity. However, it is difficult to assess heterogeneity, as the composition of tumors is dynamic and cancer treatments reshape cell diversity and gene/protein expression profiles.ObjectiveWe utilized gastric cancer patient-derived tumor organoids to monitor tumor heterogeneity and the impacts of chemotherapy (FLOT and FOLFOX) on cancer stem cells (LGR5 and CD133) and cancer immune checkpoint molecules (MHC-I and PD-L1).MethodsSix tumor organoids were established from different patients or different regions of the same tumor. The tumor organoids were used to investigate the real-time profiles of cancer stem cell marker expression and cancer immune checkpoint molecule expression after chemotherapy treatment. Tumor suppression was monitored by the propidium iodide assay and measurements of tumor organoid diameter. Expression levels of cancer stem cell markers and immune checkpoint molecules were analyzed by flow cytometry.ResultsGrowth of all tumor organoids could be suppressed by chemotherapy. However, diverse impacts of FLOT and FOLFOX were observed in terms of the expression profiles of cancer stem cell markers and cancer immune checkpoint molecules. In particular, tumor organoids from different patients exhibited distinct expression profiles for cancer stem cell markers and immune checkpoint molecules after treatment with the same chemotherapeutic regimen. Similar observations were made with tumor organoids derived the same patient but different tumor regions.ConclusionOur findings demonstrated that spatial and temporal tumoral heterogeneity can be observed after treatment with chemotherapy, suggesting that repeated monitoring of tumor characteristics may be essential for clinical decision making. In addition, sampling of multiple sites at multiple time-points might be important when evaluating the impacts of chemotherapy on cancer stem cells markers and immune checkpoint molecules.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261474427"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148649534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atypical cytokine release syndrome induced by carboplatin: The first described case report.","authors":"Maria Cruz Torres Górriz, Julian Borrás Cuartero, Anna Bosh Requena, Dah Tay Jang, Ernesto Enrique","doi":"10.1177/03946320261472669","DOIUrl":"10.1177/03946320261472669","url":null,"abstract":"<p><p>IntroductionHypersensitivity reactions to carboplatin include type I reactions, mixed reactions, and delayed reactions.Case reportWe report a case of an atypical cytokine release syndrome induced by carboplatin in a patient with breast carcinoma.Management & outcomeThe patient developed clinical manifestations consisting of a delayed cytokine release syndrome following administration of carboplatin and paclitaxel. To establish the diagnosis, she underwent a double desensitization protocol over two consecutive days with paclitaxel and carboplatin. A delayed elevation of interleukin-6 after carboplatin supported the diagnosis of an isolated cytokine release syndrome. The patient subsequently continued treatment with paclitaxel through standard infusions and with carboplatin using a desensitization protocol.DiscussionCytokine release syndrome associated with carboplatin has been previously reported as occurring immediately after infusion and as part of a mixed phenotype (type I and cytokine release). A delayed-onset cytokine release syndrome induced by carboplatin, occurring outside the context of a mixed reaction, is reported.ConclusionCytokine release syndrome may present as an isolated, delayed reaction following carboplatin infusion. Measurement of interleukin-6 may be a valuable diagnostic tool for confirming the diagnosis of cytokine release syndrome.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261472669"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reframing the gut-lung axis: Microbiota dysbiosis, immune-redox regulation, and the potential role of vitamin C.","authors":"Lunawati L Bennett","doi":"10.1177/03946320261497604","DOIUrl":"https://doi.org/10.1177/03946320261497604","url":null,"abstract":"<p><p>The respiratory system is continuously exposed to environmental antigens, pathogens, and pollutants, requiring tightly regulated immunity to balance inflammation and host defense. Increasing evidence indicates that the microbiome-within the airways and through the gut-lung axis-plays a critical role in shaping pulmonary immune responses. Microbial metabolites such as short-chain fatty acids (SCFAs), tryptophan-derived indoles, and bile acid intermediates, influence the maturation and functional programming of alveolar macrophages, dendritic cells, and T lymphocytes. Using the emerging framework of microbiota dysbiosis-related disorders, this review distinguishes descriptive microbial alterations from functionally and clinically relevant dysbiosis involving microbial metabolites, barrier integrity, immune regulation, and respiratory outcomes. Nutritional and microbiome-targeted interventions-such as dietary fiber, probiotics, and antioxidant micronutrients including vitamin C-may help restore immune homeostasis and reduce inflammatory burden through microbiota-mediated and redox-regulatory pathways. By supporting epithelial barrier integrity, modulating oxidative stress, and promoting regulatory immune signaling, vitamin C may complement microbiome-directed strategies aimed at maintaining respiratory immune resilience. The review critically synthesizes mechanistic, observational, and clinical evidence linking microbiota dysbiosis to respiratory immune homeostasis and evaluates microbiome-targeted and vitamin C-related strategies according to their current level of evidentiary support.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261497604"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shikonin improves intestinal barrier function through modulation of GPX4 expression in intestinal epithelial cells.","authors":"Fuheng Yang, Peihua Liang, Hengli Guo, Weizhao Yan, Gen Wang, Xiufu Tang, Zhen Liang","doi":"10.1177/03946320261427239","DOIUrl":"10.1177/03946320261427239","url":null,"abstract":"<p><p>Shikonin has been reported to regulate caudal-type homeobox 2 (CDX2)-mediated intestinal epithelial cell (IEC) differentiation, and ferroptosis has been identified a critical event during this process. However, the exact role of ferroptosis in shikonin-induced IEC differentiation remains unclear. Accordingly, the aim of this study was to elucidate the involvement of ferroptosis in CDX2-mediated IEC differentiation induced by shikonin. Real-time polymerase chain reaction, western blotting, luciferase assay, immunoprecipitation, and chromatin immunoprecipitation were used to reveal the mechanism underlying shikonin-modulated ferroptosis-dependent IEC differentiation in HT-29 and Caco-2 cells. Shikonin treatment reduced ferroptosis in IECs, as evidenced by the increased expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 (cationic amino acid transporter) member 11, which enhanced CDX2 expression and improved IEC barrier function. Mechanistically, shikonin activated the protein kinase A (PKA)/cAMP-responsive element-binding protein (CREB) signaling cascade, promoting CREB binding to the GPX4 promoter and initiating GPX4 transactivation. GPX4 inhibition reversed the effects of shikonin on CDX2 expression. Endogenous pyruvate kinase isozyme M2 interacted with phosphodiesterase 4; this interaction was disrupted by shikonin, leading to the activation of PKA/CREB signaling. The findings of this study indicate that a low dose of shikonin improves IEC barrier function through GPX4-mediated inhibition of ferroptosis, highlighting its potential as a therapeutic agent for intestinal mucosal injury.</p>","PeriodicalId":48647,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"40 ","pages":"3946320261427239"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147311657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}