Ideal cardiovascular health index and high-normal blood pressure in elderly people: evidence based on real-world data.

Limited information is available on the cardiovascular health (CVH) index and risk of high-normal blood pressure (HNBP) in elderly people. Randomized cluster sampling, multivariate logistic regression, and mediating effects analysis were used in this study analyze the relationship between CVH index and HNBP in the elderly. 1089 non-hypertensive residents aged 65 years or older completed the study. The positive rate of HNBP was 75.85% (male vs. female: 76.13% vs. 75.64%, P = 0.852); The ideal rate of CVH (ideal CVH index ≥ 5 items) was 14.51% (male vs. female: 15.91% vs. 13.46%, P = 0.256). Compared with people with 0-2 ideal CVH index, the risk of HNBP in people with 4 ideal indexes and ≥ 5 ideal indexes decreased by 50% and 63%, respectively, and their OR (95% CI) were 0.50 (0.31, 0.81) and 0.37 (0.21, 0.66), respectively. The results of the trend test showed that the risk of HNBP decreased by 32% for every increase in the ideal CVH index (trend P < 0.001) and TyG index does not play a mediating role in this relationship. That is, increasing the number of ideal CVH index may effectively reduce the risk of HNBP in elderly by one-third.

Stachyose Exerts Anticolitis Efficacy by Re-balancing Treg/Th17 and Activating the Butyrate-Derived PPARγ Signaling Pathway.

Ulcerative colitis (UC) is a complex chronic inflammatory disease closely associated with gut homeostasis dysfunction. The previous studies have shown that stachyose, a functional food additive, has the potential to enhance gut health and alleviate UC symptoms. However, the underlying mechanism of its effects remains unknown. In this study, our findings showed that dietary supplements of stachyose had a significant dose-dependent protective effect on colitis symptoms, regulation of gut microbiota, and restoration of the Treg/Th17 cell balance in dextran sulfate sodium (DSS) induced colitis mice. To further validate these findings, we conducted fecal microbiota transplantation (FMT) to treat DSS-induced colitis in mice. The results showed that microbiota from stachyose-treated mice exhibited a superior therapeutic effect against colitis and effectively regulated the Treg/Th17 cell balance in comparison to the control group. Moreover, both stachyose supplementation and FMT resulted in an increase in butyrate production and the activation of PPARγ. However, this effect was partially attenuated by PPARγ antagonist GW9662. These results suggested that stachyose alleviates UC symptoms by modulating gut microbiota and activating PPARγ. In conclusion, our work offers new insights into the benefical effects of stachyose on UC and its potential role in modulating gut microbiota.

GLUT3 transcriptional activation by ZEB1 fuels the Warburg effect and promotes ovarian cancer progression.

Ovarian cancer (OvCa) is characterized by early metastasis and high mortality rates, underscoring the need for deeper understanding of these aspects. This study explores the role of glucose transporter 3 (GLUT3) driven by zinc finger E-box-binding homeobox 1 (ZEB1) in OvCa progression and metastasis. Specifically, this study explored whether ZEB1 promotes glycolysis and assessed the potential involvement of GLUT3 in this process in OvCa cells. Our findings revealed that ZEB1 and GLUT3 were excessively expressed and closely correlated in OvCa. Mechanistically, ZEB1 activates the transcription of GLUT3 by binding to its promoter region. Increased expression of GLUT3 driven by ZEB1 dramatically enhances glycolysis, and thus fuels Warburg Effect to promote OvCa progression and metastasis. Consistently, elevated ZEB1 and GLUT3 expression in clinical OvCa is correlated with poor prognosis, reinforcing the profound contribution of ZEB1-GLUT3 axis to OvCa. These results suggest that activation of GLUT3 expression by ZEB1 is crucial for the proliferation and metastasis of OvCa via fueling glycolysis, shedding new light on OvCa treatment.

Multiparametric MRI-based intratumoral and peritumoral radiomics for predicting the pathological differentiation of hepatocellular carcinoma.

PURPOSE: To explore the predictive potential of intratumoral and multiregion peritumoral radiomics features extracted from multiparametric MRI for predicting pathological differentiation in hepatocellular carcinoma (HCC) patients. METHODS: A total of 265 patients with 277 HCCs (training cohort n = 193, validation cohort n = 84) who underwent preoperative MRI were retrospectively analyzed. The risk factors identified through stepwise regression analysis were utilized to construct a clinical model. Radiomics models based on MRI (arterial phase, portal venous phase, delayed phase) across various regions (entire tumor, Peri_5mm, Peri_10mm, Peri_20mm) were developed using the LASSO approach. The features obtained from the intratumoral region and the optimal peritumoral region were combined to design the IntraPeri fusion model. Model performance was assessed using the area under the curve (AUC). RESULTS: Larger size, non-smooth margins, and mosaic architecture were risk factors for poorly differentiated HCC (pHCC). The clinical model achieved AUCs of 0.77 and 0.73 in the training and validation cohorts, respectively, while the intratumoral model achieved corresponding AUC values of 0.92 and 0.82. The Peri_10mm model demonstrated superior performance to the Peri_5mm and Peri_20mm models, with AUC values of 0.87 vs. 0.84 vs. 0.73 in the training cohort and 0.80 vs. 0.77 vs. 0.68 in the validation cohort, respectively. The IntraPeri model exhibited remarkable AUC values of 0.95 and 0.86 in predicting pHCC in the training and validation cohorts, respectively. CONCLUSIONS: Our study highlights the potential of a multiparametric MRI-based radiomic model that integrates intratumoral and peritumoral features as a tool for predicting HCC differentiation. CRITICAL RELEVANCE STATEMENT: Both clinical and multiparametric MRI-based radiomic models, particularly the intratumoral radiomic model, are non-invasive tools for predicting HCC differentiation. Importantly, the IntraPeri fusion model exhibited remarkable predictiveness for individualized HCC differentiation. KEY POINTS: • Both the intratumoral radiomics model and clinical features were useful for predicting HCC differentiation. • The Peri_10mm radiomics model demonstrated better diagnostic ability than other peritumoral region-based models. • The IntraPeri radiomics fusion model outperformed the other models for predicting HCC differentiation.

Dynamic immune recovery process after liver transplantation revealed by single-cell multi-omics analysis.

Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation (LT) is critical for precise clinical management strategies. Here, we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) collected from LT patients (with and without acute cellular rejection [ACR]) at 13 time points. Validation was performed in two independent cohorts with additional LT patients and healthy controls. Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition, expression programs, and interactions along this process. The intensity of the immune response differs between the ACR and non-ACR patients. Notably, the newly identified inflamed NK cells, CD14+RNASE2+ monocytes, and FOS-expressing monocytes emerged as predictive indicators of ACR. This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery, providing a four-phase framework that aids the clinical management of LT patients.

Determination of Maximum Tolerable Cold Ischemia Time in a Mouse Model of Cervical Heterotopic Uterus Transplantation.

BACKGROUND: Uterus transplantation (UTx) is an emerging treatment for uterine factor infertility. Determining the maximum tolerable cold ischemia time is crucial for successful UTx. However, the limit for cold ischemia in the uterus is unclear. This study aimed to examine cold ischemia's effects on mouse uteri and identify the maximum cold ischemia duration that uteri can endure. METHODS: We systematically assessed the tolerance of mouse uteri to extended cold ischemia, 24 h, 36 h, and 48 h, using the cervical heterotopic UTx model. Multiple indicators were used to evaluate ischemia-reperfusion injury, including reperfusion duration, macroscopic examination, oxidative stress, inflammation, and histopathology. The function of transplants was evaluated through estrous cycle monitoring and embryo transfer. RESULTS: Mouse uteri subjected to 48 h of cold ischemia exhibited significant delays and insufficiencies in reperfusion, substantial tissue necrosis, and loss of the estrous cycle. Conversely, uteri that underwent cold ischemia within 36 h showed long survival, regular estrous cycles, and fertility. CONCLUSIONS: Our study demonstrated that mouse uteri can endure at least 36 h of cold ischemia, extending the known limits for cold ischemia and providing a pivotal reference for research on the prevention and treatment of cold ischemic injury in UTx.

Improving the Aerobic Capacity in Fingerlings of European Sea Bass (Dicentrarchus labrax) through Moderate and Sustained Exercise: A Metabolic Approach.

Sustained swimming induces beneficial effects on growth and energy metabolism in some fish species. However, the absence of a standardized exercise regimen that guarantees an optimal response to physical activity is due to the anatomical, behavioral, and physiological differences among species, and the different conditions of tests applied, which are especially notable for the early stages of cultured species. The objective of this study was to assess the growth and metabolic responses of European sea bass submitted to continuous and moderate exercise exposure, selecting a practical swimming speed from swimming tests of groups of five fingerlings. The exercise-effects trial was carried out with 600 sea bass fingerlings (3-5 g body weight) distributed in two groups (control: voluntary swimming; exercised: under sustained swimming at 1.5 body lengths·s-1). After 6 weeks, growth parameters and proximal composition of both muscles were not altered by sustained swimming, but an increased synthetic capacity (increased RNA/DNA ratio) and more efficient use of proteins (decreased ΔN15) were observed in white muscle. The gene expression of mitochondrial proteins in white and red muscle was not affected by exercise, except for ucp3, which increased. The increase of UCP3 and Cox4 protein expression, as well as the higher COX/CS ratio of enzyme activity in white muscle, pointed out an enhanced oxidative capacity in this tissue during sustained swimming. In the protein expression of red muscle, only CS increased. All these metabolic adaptations to sustained exercise were also reflected in an enhanced maximum metabolic rate (MMR) with higher aerobic scope (AMS) of exercised fish in comparison to the non-trained fish, during a swimming test. These results demonstrated that moderate sustained swimming applied to sea bass fingerlings can improve the physical fitness of individuals through the enhancement of their aerobic capacities.

A computational approach to estimate postmortem interval using postmortem computed tomography of multiple tissues based on animal experiments.

The estimation of postmortem interval (PMI) is a complex and challenging problem in forensic medicine. In recent years, many studies have begun to use machine learning methods to estimate PMI. However, research combining postmortem computed tomography (PMCT) with machine learning models for PMI estimation is still in early stages. This study aims to establish a multi-tissue machine learning model for PMI estimation using PMCT data from various tissues. We collected PMCT data of seven tissues, including brain, eyeballs, myocardium, liver, kidneys, erector spinae, and quadriceps femoris from 10 rabbits after death. CT images were taken every 12 h until 192 h after death, and HU values were extracted from the CT images of each tissue as a dataset. Support vector machine, random forest, and K-nearest neighbors were performed to establish PMI estimation models, and after adjusting the parameters of each model, they were used as first-level classification to build a stacking model to further improve the PMI estimation accuracy. The accuracy and generalized area under the receiver operating characteristic curve of the multi-tissue stacking model were able to reach 93% and 0.96, respectively. Results indicated that PMCT detection could be used to obtain postmortem change of different tissue densities, and the stacking model demonstrated strong predictive and generalization abilities. This approach provides new research methods and ideas for the study of PMI estimation.

Profiling regulatory T lymphocytes within the tumor microenvironment of breast cancer via radiomics.

OBJECTIVE: To generate an image-driven biomarker (Rad_score) to predict tumor-infiltrating regulatory T lymphocytes (Treg) in breast cancer (BC). METHODS: Overall, 928 BC patients were enrolled from the Cancer Genome Atlas (TCGA) for survival analysis; MRI (n = 71 and n = 30 in the training and validation sets, respectively) from the Cancer Imaging Archive (TCIA) were retrieved and subjected to repeat least absolute shrinkage and selection operator for feature reduction. The radiomic scores (rad_score) for Treg infiltration estimation were calculated via support vector machine (SVM) and logistic regression (LR) algorithms, and validated on the remaining patients. RESULTS: Landmark analysis indicated Treg infiltration was a risk factor for BC patients in the first 5 years and after 10 years of diagnosis (p = 0.007 and 0.018, respectively). Altogether, 108 radiomic features were extracted from MRI images, 4 of which remained for model construction. Areas under curves (AUCs) of the SVM model were 0.744 (95% CI 0.622-0.867) and 0.733 (95% CI 0.535-0.931) for training and validation sets, respectively, while for the LR model, AUCs were 0.771 (95% CI 0.657-0.885) and 0.724 (95% CI 0.522-0.926). The calibration curves indicated good agreement between prediction and true value (p > 0.05), and DCA shows the high clinical utility of the radiomic model. Rad_score was significantly correlated with immune inhibitory genes like CTLA4 and PDCD1. CONCLUSIONS: High Treg infiltration is a risk factor for patients with BC. The Rad_score formulated on radiomic features is a novel tool to predict Treg abundance in the tumor microenvironment.

Coincidence of Systemic Lupus Erythematosus and ANCA-Associated Vasculitis: A Case Report with Perforation of Nasal Septum and Palate.

Background: An overlap of systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibodies- (ANCA-) associated vasculitis (AAV) is extremely uncommon and no clear definition has been proposed. The SLE/AAV overlap syndrome mainly affects kidney, blood count, nervous system and lung. However, few previous cases reported nasal septal and palatal perforation in this disorder. Case Presentation: We presented a case of a 16-year-old female with a 6-month history of SLE, developed perforation of the nasal septum and palate. She was diagnosed with SLE due to facial malar rash, oral ulcer, increased erythrocyte sedimentation rate (ESR), low complement levels, and positive anti-Smith antibody. Approximately 6 months later, she had a perforation of the nasal septum and palate with positive anti-proteinase 3 antibody (anti-PR3-ANCA). A nasal endoscopic biopsy revealed an inflammatory polyp with chronic suppurative inflammation and inflammatory granulomatous hyperplasia. In this case, the clinical, biological, radiological, and histological findings substantiated the diagnosis of AAV. Infections, drug abuse, malignancies, IgG4-related disease (IgG4-RD) and trauma were excluded. So we diagnosed her with SLE/AAV overlap syndrome. Conclusion: When a patient's symptoms cannot be explained by one disease, we need to consider the overlapping of two diseases, especially in patients with autoimmune diseases.

Contrast-Enhanced Mammography Radiomics Analysis for Preoperative Prediction of Breast Cancer Molecular Subtypes.

BACKGROUND: Predicting breast cancer molecular subtypes can help guide individualised clinical treatment of patients who need the rational preoperative treatment. This study aimed to investigate the efficacy of preoperative prediction of breast cancer molecular subtypes by contrast-enhanced mammography (CEM) radiomic features. METHODS: This retrospective two-centre study included women with breast cancer who underwent CEM preoperatively between August 2016 and May 2022. We included 356 patients with 386 lesions, which were grouped into training (n = 162), internal test (n = 160) and external test sets (n = 64). Radiomics features were extracted from low-energy (LE) images and recombined (RC) images and selected. Three dichotomous tasks were established according to postoperative immunohistochemical results: Luminal vs. non-Luminal, human epidermal growth factor receptor (HER2)-enriched vs. non-HER2-enriched, and triple-negative breast cancer (TNBC) vs. non-TNBC. For each dichotomous task, the LE, RC, and LE+RC radiomics models were built by the support vector machine classifier. The prediction performance of the models was assessed by the area under the receiver operating characteristic curve (AUC). Then, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the models. DeLong's test was utilised to compare the AUCs. RESULTS: Radiomics models based on CEM are valuable for predicting breast cancer molecular subtypes. The LE+RC model achieved the best performance in the test set. The LE+RC model predicted Luminal, HER2-enriched, and TNBC subtypes with AUCs of 0.93, 0.89, and 0.87 in the internal test set and 0.82, 0.83, and 0.69 in the external test set, respectively. In addition, the LE model performed more satisfactorily than the RC model. CONCLUSION: CEM radiomics features can effectively predict breast cancer molecular subtypes preoperatively, and the LE+RC model has the best predictive performance.

Pectic oligosaccharides ameliorate high-fat diet-induced obesity and hepatic steatosis in association with modulating gut microbiota in mice.

Accumulating evidence has shown that gut microbiota and its metabolites have important significance in the etiology of obesity and related disorders. Prebiotics prevent and alleviate obesity by modulating the gut microbiota. However, how pectin oligosaccharides (POS) derived from pectin degradation affect gut microbiota and obesity remains unclear. To investigate the potential anti-obesity effects of POS, mice were fed a high-fat diet (HFD) for 12 weeks and a POS supplement with drinking water during the last 8 weeks. The outcomes demonstrated that POS supplementation in HFD-fed mice decreased body weight (P < 0.01), improved glucose tolerance (P < 0.001), reduced fat accumulation (P < 0.0001) and hepatic steatosis, protected intestinal barrier, and reduced pro-inflammatory cytokine levels. After fecal metagenomic sequencing, the POS corrected the gut microbiota dysbiosis caused by the HFD, as shown by the increased populations of Bifidobacterium, Lactobacillus taiwanensis, and Bifidobacterium animalis, and decreased populations of Alistipes and Erysipelatoclostridium, which were previously considered harmful bacteria. Notably, the changed gut microbiota was associated with the obesity prevention of POS. These findings demonstrate that POS regulates particular gut microbiota, which is essential owing to its ability to prevent disorders associated with obesity.

Manipulating TGF-ß signaling to optimize immunotherapy for cervical cancer.

Cervical cancer is a serious threat to women's health globally. Therefore, identifying key molecules associated with cervical cancer progression is essential for drug development, disease monitoring, and precision therapy. Recently, TGF-ß (transforming growth factor-beta) has been identified as a promising target for cervical cancer treatment. For advanced cervical cancer, TGF-ß participates in tumor development by improving metastasis, stemness, drug resistance, and immune evasion. Accumulating evidence demonstrates that TGF-ß blockade effectively improves the therapeutic effects, especially immunotherapy. Currently, agents targeting TGF-ß and immune checkpoints such as PD-L1 have been developed and tested in clinical studies. These bispecific antibodies might have the potential as therapeutic agents for cervical cancer treatment in the future.

Polysaccharides from Paecilomyces hepiali Prevent Acute Colitis in Association with Modulating Gut Microbiota and Treg/Th17 Immune Balance in Mice.

Cordyceps exopolysaccharide (CEP) has shown emerging potential in adjustment of gut microbiota and immune cell function. In this study, a water-soluble CEP with a molecular weight of 58.14 kDa was extracted from the fermentation broth of Paecilomyces hepiali, an endophytic fungus of Cordyceps sinensis. Our results indicated that Paecilomyces hepiali polysaccharide (PHP) showed significantly preventive potential on dextran sulfate sodium (DSS)-induced colitis in mice, which can prevent colon shortening, reduce intestinal epithelial cell (IEC) destruction, suppress inflammatory cell infiltration, and regulate the balance between regulatory T (Treg) cells and T helper type 17 (Th17) cells. Meanwhile, the disturbed gut microbiota was partially restored after PHP treatment. Further Pearson correlation coefficient analyses exhibited that the alteration of the gut microbiota was significantly related to adjustment of the IEC barrier and Treg/Th17 balance. In conclusion, all findings proposed that purified PHP has the potential to develop into a promising agent for colitis prevention and adjuvant therapy via maintaining intestinal homeostasis of gut microbiota and immune system.

ZEB1 Transcriptionally Activates PHGDH to Facilitate Carcinogenesis and Progression of HCC.

BACKGROUND & AIMS: Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the de novo serine synthesis pathway (SSP), has been implicated in the carcinogenesis and metastasis of hepatocellular carcinoma (HCC) because of its excessive expression and promotion of SSP. In previous experiments we found that SSP flux was diminished by knockdown of zinc finger E-box binding homeobox 1 (ZEB1), a stimulator of HCC metastasis, but the underlying mechanism remains largely unknown. Here, we aimed to determine how SSP flux is regulated by ZEB1 and the contribution of such regulation to carcinogenesis and progression of HCC. METHODS: We used genetic mice with Zeb1 knockout in liver specifically to determine whether Zeb1 deficiency impacts HCC induced by the carcinogen diethylnitrosamine plus CCl4. We explored the regulatory mechanism of ZEB1 in SSP flux using uniformly-labeled [13C]-glucose tracing analyses, liquid chromatography-mass spectrometry, real-time quantitative polymerase chain reaction, luciferase report assay, and chromatin immunoprecipitation assay. We determined the contribution of the ZEB1-PHGDH regulatory axis to carcinogenesis and metastasis of HCC by cell counting assay, methyl thiazolyl tetrazolium (MTT) assay, scratch wound assay, Transwell assay, and soft agar assay in vitro, orthotopic xenograft, bioluminescence, and H&E assays in vivo. We investigated the clinical relevance of ZEB1 and PHGDH by analyzing publicly available data sets and 48 pairs of HCC clinical specimens. RESULTS: We identified that ZEB1 activates PHGDH transcription by binding to a nonclassic binding site within its promoter region. Up-regulated PHGDH augments SSP flux to enable HCC cells to be more invasive, proliferative, and resistant to reactive oxygen species and sorafenib. Orthotopic xenograft and bioluminescence assays have shown that ZEB1 deficiency significantly impairs the tumorigenesis and metastasis of HCC, and such impairments can be rescued to a large extent by exogenous expression of PHGDH. These results were confirmed by the observation that conditional knockout of ZEB1 in mouse liver dramatically impedes carcinogenesis and progression of HCC induced by diethylnitrosamine/CCl4, as well as PHGDH expression. In addition, analysis of The Cancer Genome Atlas database and clinical HCC samples showed that the ZEB1-PHGDH regulatory axis predicts poor prognosis of HCC. CONCLUSIONS: ZEB1 plays a crucial role in stimulating carcinogenesis and progression of HCC by activating PHGDH transcription and subsequent SSP flux, deepening our knowledge of ZEB1 as a transcriptional factor in fostering the development of HCC via reprogramming the metabolic pathway.

TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation.

It has been reported that deletion of tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2, TIPE2) facilitates the activation of T-cell receptors. However, the role of TIPE2 in T-cell-mediated acute transplant rejection remains unclear. To illustrate the underlying cellular mechanisms, we transplanted BALB/c hearts into C57BL/6 wild-type (WT) or C57BL/6 mice deficient for TIPE2 (TIPE2-/-) and found that TIPE2-/- recipient mice showed significantly prolonged survival of heart allografts and suppressed maturation of CD11c+ dendritic cells (DCs), which largely abolished the activation and proliferation of alloreactive T cells and their cytotoxic activity. TIPE2-/- DCs increased CD4+CD25+Foxp3+CD127- regulatory T cells (Tregs)generation, likely by inhibiting DCs maturation and CD80 and CD86 expression. Administration of anti-CD25 abolished the allograft survival induced by TIPE2 deficiency. Moreover, TIPE2 deficiency increased IL-10 production in T cells and in recipient serum and allografts. Mechanistic studies revealed that TIPE2-/- restrained the maturation of DCs via inhibition of PI3K/AKT phosphorylation during alloantigen stimulation. Taken together, TIPE2 deficiency in recipient mice inhibited acute rejection by increasing Tregs generated by immature DCs. Thus, TIPE2 could be a therapeutic target for suppressing rejection in organ transplantation.

Mapping the knowledge of traffic collision Reconstruction: A scientometric analysis in CiteSpace, VOSviewer, and SciMAT.

Traffic collisions are incidents with high fatality rate which generate billions of US dollars of loss worldwide each year. Post-collision scene reconstruction, which involves knowledge of multiple disciplines, is an important approach to restore the traffic collision and infer the cause of it. This paper uses software CiteSpace, VOSviewer, and SciMAT to conduct a visualization study of knowledge mapping on the literature of traffic collision scene reconstruction from 2001 to 2021 based on the Web of Science database. Knowledge mapping is a cutting-edge research method in scientometric, which has been widely applied in medicine and informatics. Compared with traditional literature review, knowledge mapping with visual techniques identifies hot keywords and key literature in the field more scientifically, and displays them in schematic diagrams intuitively which allows to further predict potential hotspots. A total of 803 original papers are retrieved to analyze and discuss the evolution of the field in the past 20 years, from macro to micro, in term of background information, popular themes, and knowledge structure. Results indicate the number of publications in this field is limited, and collaborations among authors and among institutions are insufficient. In the meantime, mappings imply the top three hot themes being scene reconstruction, computer technology, and injuries. The introduction of AI related technologies, such as neural networks and genetic algorithms, into collision reconstruction would be a potential research direction.

TIPE2 knockout reduces myocardial cell damage by inhibiting IFN-γ-mediated ferroptosis.

Acute rejection of the transplanted heart is mediated by oxidative programmed cell death through the synergistic effects of the innate and adaptive immune systems. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been widely evaluated. Tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2), also known as TIPE2, is required for maintaining immune homeostasis. To characterize the role of TIPE2 in mediating heart allografts, BALB/c hearts were transplanted into C57BL/6 wild-type (WT) and TIPE2-/- recipient mice. In TIPE2-/- recipient mice, allograft injury in BALB/c allograft hearts was significantly reduced through the inhibition of allograft ferroptosis. On day 3 and day 6 post-transplantation, the numbers of CD3+, CD4+, and CD8+ cells among splenocytes and draining lymph node cells were significantly decreased, and the activation of CD4+ and CD8+ cells in grafts was decreased in TIPE2-/- recipient mice compared with WT mice. Moreover, CD4+ and CD8+ T cells in TIPE2-/- recipient mice were characterized by deficient capacities for interferon-γ (IFN-γ) production through the TBK1 signaling axis and increased glutathione peroxidase 4 (GPX4). In cell experiments, treatment with IFN-γ enhanced ferroptosis-specific lipid peroxidation in myocardial cells and correlated inversely with GPX4 expression. Mechanistically, IFN-γ administration decreased the expression of GPX4 by inhibiting MEK/ERK phosphorylation. In summary, our findings demonstrated that TIPE2 deficiency inhibits T-cell production of IFN-γ to reduce ferroptosis in allografts by restraining lipid peroxidation.