BACKGROUND:Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood. OBJECTIVE:To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC. DESIGN:We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens. RESULTS:TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8+ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8+ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis. CONCLUSION:Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

Lysine acetylation affects hepatocellular carcinoma (HCC) malignancy through multiple pathways. Evidence from our laboratory and other groups indicates that long chain acyl CoA synthetase 4 (ACSL4) is a crucial oncoprotein in HCC. However, the precise mechanisms underlying the post-translational regulation of ACSL4 acetylation remains unknown. Here, we report a previously unknown mechanism of ACSL4 regulation involving acetylation at the lysine 49 (K49) site by the acetyltransferase MOF. ACSL4 acetylation hindered its degradation via the ubiquitin-proteasome pathway. Using mass spectrometry and subsequent verification, we demonstrated that TRIM21 is an E3 ubiquitin ligase responsible for ACSL4 proteasomal degradation. Further mechanistic studies revealed that MOF-mediated ACSL4-K49 acetylation counteracted the TRIM21-mediated degradation of ACSL4. Functionally, we demonstrated that acetylated ACSL4 promotes lipid accumulation and HCC progression, both in vitro and in vivo. Clinically, ACSL4-K49 acetylation is frequently increased in HCC samples, and elevated ACSL4-K49 acetylation is associated with poor prognosis in patients with HCC. Together, these findings unveil a novel regulatory mechanism of ACSL4, highlighting its pivotal role in modulating HCC progression.

Ischemic stroke triggers a cascade of mitochondrial dysfunction, oxidative stress, neuroinflammation, and pyroptosis, ultimately leading to neuronal injury and neurological deficits. Therapeutic efficacy is often limited by inadequate blood–brain barrier penetration and off-target effects. To address these challenges, we designed 3R@Lipo/Gink, a biocompatible liposomal formulation modified with an ROS-responsive TK polymer and two functional peptides—RVG29 for enhanced brain delivery and MG1 for microglia enrichment—to enable precise transport of ginkgetin, which has been demonstrated to exert neuroprotective effects through multiple potential mechanisms, to ischemic lesions.In a middle cerebral artery occlusion/reperfusion model, 3R@Lipo/Gink markedly reduced infarct size, alleviated neuronal injury, and improved motor performance. Single-cell RNA sequencing and in vitro co-culture experiments identified microglia and neurons as the primary responsive cell types. Mechanistic studies showed that 3R@Lipo/Gink suppressed HIF-1α expression, thereby downregulating c-myc–mediated microglial proliferation and attenuating NLRP3-dependent pyroptosis. These protective effects were reversed by FG-4592, a prolyl hydroxylase inhibitor that stabilizes HIF-1α, supporting the involvement of the HIF-1α pathway. Through mitigating microglial overactivation and interrupting the inflammatory-pyroptotic loop, 3R@Lipo/Gink ultimately remodels the microglia-mediated inflammatory microenvironment around neurons and improves functional recovery.These findings highlight 3R@Lipo/Gink as a promising targeted nanotherapeutic strategy for ischemic stroke and other nervous system diseases.

INTRODUCTION:Cytochrome P450 2E1 (CYP2E1) plays a crucial role in metabolism and disease, making it highly significant to establish a simpler, sensitive method for evaluating its in vivo activity compared to traditional pharmacokinetic (PK) parameters. METHODS:A high-performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated for determining chlorzoxazone (CZX) and its metabolite 6-hydroxy CZX (6-OH CZX) in plasma. Four mouse models with distinct CYP2E1 activity were constructed: high activity induced by isoniazid, and low activity via Q11 (a CYP2E1 inhibitor), Cyp2e1 knockout, or carbon tetrachloride (CCl₄). PK experiments were conducted, with activity changes verified by in vitro CYP2E1 protein expression and microsomal activity. Additionally, the sensitivity of PK parameters and the plasma 6-OH CZX/CZX ratio (metabolite ratio, MR) for characterizing CYP2E1 activity, as well as correlations between MR at different time points and both microsomal CYP2E1 activity and CZX half-life (t₁/₂), were analyzed. RESULTS:The HPLC-UV method met analytical requirements in terms of specificity, linearity, and intra-day and inter-day precision. Microsomal activity and protein expression experiments confirmed the successful establishment of the four models. For CYP2E1 activity characterization, CZX t₁/₂ was more sensitive than its area under the curve (AUC) and clearance (CL); MR values at 15 and 7 minutes outperformed those at 2 minutes, with 15-minute MR showing stronger correlations with microsomal activity (r = 0.57, P = 0.007) and CZX t₁/₂ (r = 0.83, P < 0.01). DISCUSSION:This study addresses limitations of traditional PK parameters (multiple samplings, non-metabolic interference) and existing MR methods (unclear optimal time points). The 15-min MR and CZX t₁/₂ offer simplified evaluation, with CZX's high CYP2E1 specificity enhancing translation. Limitations include focus on male C57BL/6J mice and single-point MR's inability to reflect dynamic activity. CONCLUSION:Four representative mouse models with distinct CYP2E1 activity were successfully constructed. CZX t₁/₂ exhibits higher sensitivity and applicability in characterizing in vivo CYP2E1 activity changes, while the 15-minute MR better represents activity changes. This research lays a foundation for characterizing CYP2E1 variations in disease and pathological processes.

Background: Hepatocellular carcinoma (HCC), a highly aggressive malignancy with poor prognosis, is characterized by hyperactivation of the epidermal growth factor receptor (EGFR) signaling pathway. Glutaminase (GLS) is commonly overexpressed in numerous malignant tumors and acts as an oncogene to support cell growth and tumor progression, making it a target for cancer treatment. This study aimed to elucidate the underlying mechanisms of EGFR activation in driving glutaminolysis reprogramming and conferring ferroptosis resistance in HCC. Methods: Untargeted metabolomics, stable isotope-assisted metabolomic analysis, and RNA sequencing analysis were utilized to elucidate the mechanisms underlying glutaminolysis reprogramming upon EGFR activation. Immunoprecipitation, RNA pulldown, and dual-luciferase reporter assays were employed to examine the regulatory role of Wilms' tumor 1-associated protein (WTAP) phosphorylation in GLS alternative splicing. Flow cytometry, cell viability assays, tumor-bearing mouse models, and HCC clinical specimens were used to validate the role of the AKT-WTAP-GLS axis in ferroptosis resistance and tumor progression. Results: Here, we demonstrated that AKT activated by EGFR signaling phosphorylated WTAP S176 and increased WTAP binding to methyltransferase-like protein 3. The enhanced interaction promoted the site-specific N6-methyladenosine (m6A) modification of GLS pre-mRNA, which in turn favored the alternative splicing of GLS toward glutaminase C (GAC) over kidney-type glutaminase. This switch led to increased glutamine utilization and glutathione/nicotinamide adenine dinucleotide phosphate (reduced form) biosynthesis, thereby alleviating ferroptosis and promoting tumor growth in mice. In addition, the levels of WTAP pS176 and GAC expression, which were mutually correlated, were positively associated with poor prognosis of patients with HCC. Conclusions: These findings uncover a critical mechanism by which tumor cells counteract ferroptosis by WTAP-mediated GLS alternative splicing under EGFR activation, highlighting the therapeutic potential of targeting the m6A-dependent GLS isoform switch in HCC and offering a rationale for the development of combination therapies.

IntroductionAs an immune checkpoint molecule that is overexpressed in cervical and breast cancer, CD155 represents an attractive target for chimeric antigen receptor (CAR) T-cell therapy. However, it is crucial to thoroughly assess the efficacy and safety of CD155-based CAR T cells in preclinical models before considering clinical translation.MethodsIn this study, we developed a CD155-based CAR comprising the extracellular domain of the human TIGIT, 4-1BB, and CD3z signaling domains and utilized a murine model of cervical and breast cancer to comprehensively evaluate the antitumor responses elicited by the CD155-based CAR T cells. The CAR construct was specifically designed to recognize and target CD155-expressing tumor cells.ResultsThe results of our study indicated that CD155 exhibits positive staining in the majority of clinical cervical and breast cancer tissues while showing no or low staining in normal tissues. In addition, we observed a correlation between the expression level of CD155 and the proliferation of malignant tumor cells. CD155-based CAR T cells effectively recognize and eliminate CD155-expressing tumor cells in vitro. Moreover, in vivo experiments using a murine model of cervical and breast cancer revealed that the administration of these CAR T cells leads to significant regression of established tumors without causing any observable toxicity. In addition, the clearance of CD155-positive tumor cells can effectively eliminate tumor cells that exhibit high proliferation rates. This suggests that the treatment approach may offer a safe and effective option for patients with cervical and breast cancer.DiscussionOverall, our findings provide strong evidence for the efficacy and safety of CD155-based CAR T-cell therapy in cervical and breast cancer. This study contributes to the growing body of research supporting the potential clinical application of CD155-targeted immunotherapy for patients with cervical and breast cancer.

Current studies found that the peritumoral tissue of hepatocellular carcinoma (HCC) may be different from normal liver tissue based on proteomics, and related to progression, recurrence and metastasis of HCC. Our previous study proposed “peritumor microenvironment (PME)” to summarize the influence of peritumor tissue on occurrence and progression of HCC. Peritumor CYP2E1 activity was significantly elevated in HCC, and related to occurrence and progression of HCC. However, the effectiveness and mechanism of inhibiting CYP2E1 against HCC remain unclear. In this study, by integrating the advantages of proteomics and transcriptomics, we reanalyzed the various influencing factors in PME. Although there were large differences in the occurrence and progression, the immunity and inflammation still played crucial roles. Peritumor neutrophil were “pro-tumor” phenotype in the stage of progression, while it showed cytotoxicity for tumor cell in the occurrence stage. CYP2E1 activity is associated with peritumor neutrophil infiltration and occurrence of HCC. CYP2E1 inhibitor Q11 showed anti-tumor effects in an orthotopic HCC mouse model by promoting secretion of chemokines and infiltration of neutrophils in peritumor tissue. Overall, these findings provided a reasonable mechanism of anti-tumor effects of CYP2E1 inhibitors, which may be a new strategy for the prevention and treatment of HCC.

Tumors remain one of the major challenges confronting researchers today. The development of tumor is driven by genetic factors, environmental exposures, and homeostatic disruptions, leading to the transformation of normal cells into malignant ones. Natural killer (NK) cells, a crucial class of immune cells in immunotherapy, can directly recognize and eliminate tumor cells without prior stimulation by tumor antigens. Exosomes derived from NK cells exert anti-tumor effects through multiple mechanisms, including the release of cytotoxic molecules, death receptor ligand-mediated apoptosis, and the secretion of cytokines and other bioactive molecules. However, the therapeutic efficacy of unmodified exosomes is constrained by insufficient active components, suppression by the tumor microenvironment, and a lack of targeting specificity. Drug loading and engineering strategies can enhance their therapeutic potential. In this review, we examine advancements in NK cell-derived exosome (NK-Exos)-based anti-tumor strategies, focusing on studies involving native exosomes, drug-loaded exosomes, and surface-modified exosomes for tumor eradication.

Natural killer (NK) cells are crucial for immune defense against tumors, but their function is often impaired in the tumor microenvironment. High mobility group box 2 (HMGB2), a chromatin-associated protein, is implicated in various cancers, yet its role in regulating NK cells, particularly in esophageal squamous cell carcinoma (ESCC), is unclear. We conducted transcriptomic and proteomic analyses of peripheral blood mononuclear cells (PBMCs) from ESCC patients and healthy donors to identify immunoregulatory molecules. Flow cytometry confirmed upregulation of HMGB2 in NK cells from ESCC patients, correlating with advanced tumor stage. Using RNA interference, CRISPR/Cas9, and overexpression methods, we modulated HMGB2 in NK-92 cells and assessed their cytotoxicity against ESCC cells. HMGB2 silencing or knockout enhanced NK cell cytotoxicity, evidenced by increased granzyme B, perforin, IFN-γ, and TNF-α, and higher tumor cell lysis. Conversely, HMGB2 overexpression suppressed these effects. Mechanistically, HMGB2 ablation induced ANGPT1 expression and activated the PI3K/AKT pathway. ANGPT1 knockdown in KO-HMGB2 NK cells reduced PI3K/AKT activation, confirming the involvement of the ANGPT1/PI3K/AKT axis in enhanced NK cell function. These results indicate that HMGB2 inhibits NK cell-mediated anti-tumor immunity in ESCC. HMGB2 depletion enhances NK cell cytotoxicity via the ANGPT1/PI3K/AKT pathway, suggesting its potential as a therapeutic target to improve NK cell-based immunotherapy in ESCC.

While NUSAP1's association with various tumors is established, its predictive value for prognosis and immunotherapy in lung adenocarcinoma (LUAD) remains unconfirmed. We analyzed Nucleolar Spindle-Associated Protein 1 (NUSAP1) gene expression in TCGA and GTEx datasets and validated it in clinicopathological tissues using qRT-PCR and immunohistochemistry. Additionally, we investigated NUSAP1's relationship with patient prognosis across TCGA and five GEO cohorts. The IMvigor210 cohort was utilized to explore NUSAP1's association with immunotherapy efficacy. Furthermore, single-cell RNA-sequencing data was used to examine the correlation between NUSAP1 and immune cell infiltration. Finally, we analyzed the relationship between NUSAP1 and m6A methylation. NUSAP1 expression was significantly elevated in tumor tissues, correlating with poorer prognosis in LUAD patients. It exhibited a significant correlation with immune cell infiltration in the tumor microenvironment, predominantly expressed in Tprolif cells. LUAD patients with heightened NUSAP1 expression may derive greater benefit from anti-PD-L1 treatment. Additionally, NUSAP1 was tightly linked with m6A methylation. Enrichment analysis revealed its association with key biological functions, including lipid metabolism and cell cycle regulation. Our comprehensive analysis underscores NUSAP1's potential as a prognostic and immunotherapeutic biomarker for LUAD, warranting further investigation.

Despite intensive multimodal therapy, the prognosis for patients with digestive system cancers remains poor. Cancer cell heterogeneity and immunosuppressive microenvironments are the main barriers to the effective CAR-T cell therapy with solid malignancies. In parallel, tumor-associated macrophages (TAMs) are essential for tumor immunosuppressive microenvironment formation. The limited efficacy of CAR-T cell therapy with solid malignancies prompted us to test whether new therapeutic target could enhance the antitumor activity of CAR-T cells with several digestive system cancer types. We determined CD155 expression in multiple human digestive system cancers, including gastric cancer, esophagus cancer, pancreatic cancer, and colon cancer, normal tissue samples and patient-derived M2-like tumor-associated macrophages. We developed a CD155-based CAR comprising the extracellular domain of human TIGIT, 4-1BB, and CD3z signaling domains (BBz). Furthermore, we validated the killing efficacy and safety of CD155-BBz CAR-T cells in vitro and in vivo using in-house established preclinical tumor models. CD155 was strongly and homogenously expressed in digestive system cancers but mildly in normal tissues, indicating it could be an ideal target for CAR-T cell therapy, moreover, TAMs that express CD155 possess an immunosuppressive M2-like profile. We found that CD155-BBz CAR-T cells can mediate significant antitumor activity in vivo, which induces complete tumor regression and long-lasting immunologic memory of established solid tumors in xenograft models. Our study indicates that CD155 is a promising target for digestive system cancer therapy, and CD155-targeting CAR-T cells perform a detecting power in digestive system cancer clinical trials.

Bladder outlet obstruction (BOO) is the primary clinical manifestation of benign prostatic hyperplasia, the most common urinary system disease in elderly men, and leads to associated lower urinary tract symptoms. Although BOO is reportedly associated with increased systemic oxidative stress (OS), the underlying mechanism remains unclear. The elucidation of this mechanism is the primary aim of this study. A Sprague–Dawley rat model of BOO was constructed and used for urodynamic monitoring. The bladder tissue of rats was collected and subjected to real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), histological examination, and immunohistochemical staining. Through bioinformatics prediction, we found that transforming growth factor β2 (TGFβ2) expression was upregulated in rats with BOO compared with normal bladder tissue. In vitro analyses using primary bladder smooth muscle cells (BSMCs) revealed that hydrogen peroxide (H 2 O 2 ) induced TGFβ2 expression. Moreover, H 2 O 2 induced epithelial-to-mesenchymal transition (EMT) by reducing E-cadherin, an endothelial marker and CK-18, a cytokeratin maker, and increasing mesenchymal markers, including N-cadherin, vimentin, and α-smooth muscle actin (α-SMA) levels. The downregulation of TGFβ2 expression in BSMCs using siRNA technology alleviated H 2 O 2 -induced changes in EMT marker expression. The findings of the study indicate that TGFβ2 plays a crucial role in BOO by participating in OS-induced EMT in BSMCs.

In recent years, epigenetic modifications have been strongly linked to tumor development, with histone modifications representing a key epigenetic mechanism. In addition, non-coding RNAs (ncRNAs) play a critical role in regulating cancer-related pathways. The abnormal interaction between histone modifications and ncRNAs, both pivotal epigenetic regulators, has been widely observed across various cancer types. Here, we systematically explore the molecular mechanisms through which histone modifications and ncRNAs contribute in the pathogenesis of digestive system cancers, and aberrant ncRNA-mediated histone modifications manipulate various biological behaviors of tumor cells including proliferation, migration, angiogenesis, etc. In addition, we provide new insights into diagnostic, prognostic markers, therapeutic targets and chemoradiation resistance for digestive system cancers from the epigenetic perspective.

Objective: Lung adenocarcinoma (LUAD) is a prominent contributor to global cancer mortality, characterized by constrained prognosis. This study aimed to develop a novel prognostic indicator, the Cell Death Index (CDI), utilizing twelve programmed cell death (PCD) pattern genes, to predict the immune infiltration and prognosis in LUAD patients. Methods: We collected PCD-related genes and identified prognostic PCD genes in the Cancer Genome Atlas (TCGA)-LUAD dataset, and made rigorous validation in the Clinical Proteomic Tumor Analysis Consortium (CPTAC)-LUAD cohorts. CDI was calculated using a multivariable Cox regression model. Functional enrichment and tumor microenvironment were evaluated. Drug sensitivity prediction and nomogram development were performed to assess CDI’s potential value. Results: The results revealed 10 PCD genes (ERO1A, CDK5R1, TRIM6, DNASE2B, ITPRIP, MRGPRX2, FGA, NDUFA13, NLRP2, and CD68) significantly associated with LUAD prognosis. The CDI was constructed and showed high accuracy in predicting patient survival with C-index values of 0.801 and 0.794 in the prognosis cohort and validation cohort, respectively. CDI is also indicative of variations in biological functions, tumor microenvironment, and immune cell infiltration including neutrophils, activated mast cells, activated dendritic cells, M0 macrophages, resting natural killer cells, γδT cells, and activated memory CD4+T cells. Furthermore, drug sensitivity analysis indicated potential targeted strategies. Conclusions: The CDI, based on PCD genes, serves as a robust prognostic tool for LUAD, offering profound insights into tumor biology, immune response, and personalized treatment strategies. This study underscores the pivotal role of PCD mechanisms in LUAD pathogenesis and identifies potential therapeutic targets.

This study aims to investigate the effect of cell division cycle 20 (CDC20) in gastric cancer (GC) and to explore the impact of CDC20 on the clinicopathology and prognosis of GC. The data on GC and corresponding clinical traits were downloaded from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. METHODS: Firstly, CDC20 was screened by taking eight topological analysis methods. It was also screened by Lasso regression analysis. Meanwhile, we also applied a limma package to analyze the expression of CDC20 in the normal and GC tissues. After that, we used the logistic regression method to investigate the relevance between CDC20 and the clinical characteristics. Finally, survival analysis was performed using the “survival” package, and we analyzed the prognostic value of CDC20 by single-factor and multi-factor Cox analyses. We also studied the molecular mechanism of CDC20 using multifactorial gene set enrichment analysis (GSEA). RESULTS: The expression level of CDC20 was significantly higher in GC tissues than in normal tissues, suggesting that CDC20 was highly expressed in GC. Logistic regression analysis showed that CDC20 was highly associated with staging and grading. The survival analysis revealed that high expression of CDC20 was associated with poor prognosis in GC patients. The results of single-factor and multi-factor Cox analyses suggested that CDC20 was an independent prognostic marker for GC patients. GSEA showed that CDC20 was participated in prostate cancer, small-cell lung cancer, GC, Wingless / Integrated (WNT) and T-cell receptor signaling pathway. CONCLUSION: CDC20 may be an independent prognostic marker for GC, and CDC20 is expected to be a new target for molecularly targeted therapy.

Extensive research has shown that PR domain 16 (PRDM16) plays a critical role in adipose tissue metabolism, including processes such as browning and thermogenesis of adipocytes, beigeing of adipocytes, and adipogenic differentiation of myoblasts. These functions have been associated with diseases such as obesity and diabetes. Additionally, PRDM16 has been correlated with various other conditions, including migraines, heterochromatin abnormalities, metabolic syndrome, cardiomyopathy, sarcopenia, nonsyndromic cleft lip, and essential hypertension, among others. However, there is currently no systematic or comprehensive conclusion regarding the mechanism of PRDM16 in human tumours, including haematologic and solid tumours. The aim of this review is to provide an overview of the research progress on PRDM16 in haematologic and solid tumours by incorporating recent literature findings. Furthermore, we explore the prospects of PRDM16 in the precise diagnosis and treatment of human haematologic and solid tumours.

Immunity-related GTPase M (IRGM), an Interferon-inducible protein, functions as a pivotal immunoregulator in multiple autoimmune diseases and infection. However, the role of IRGM in hepatocellular carcinoma (HCC) development remains unveiled. Here, we found interferon-γ (IFN-γ) treatment in HCC drastically triggered the expression of IRGM, and the high level of IRGM indicated poor prognosis in HCC patients. Functionally, IRGM promoted the malignant progression of HCC. Single-cell sequencing revealed that IRGM inhibition promoted the infiltration of CD8+ cytotoxic T lymphocytes (CTLs) with significant downregulation of PD-L1 expression in HCC. Furthermore, Immunoprecipitation-Mass Spectrometry assay revealed that IRGM interacted with transcription factor YBX1, which facilitated PD-L1 transcription. Mechanistically, IRGM promoted the interaction of YBX1 and phosphokinase S6K1, increasing phosphorylation and nuclear localization of YBX1, transcription of PD-L1. Additionally, the combination of IRGM inhibition with α-PD1 demonstrated a stronger anti-tumor effect compared to the single application of α-PD1. In summary, IRGM is a novel regulator of PD-L1, which suppresses CD8+ CTLs infiltration and function in HCC, resulting in cancer progression. This study may raise a novel therapeutic strategy combined with immune checkpoint inhibitors (ICIs) against HCC.

Aim: To explore the effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) and their conditioned medium (MSC-CM) in repairing the endometritis mouse model in vivo. Methods: Lipopolysaccharide (LPS) was used to induce acute inflammation in endometritis mouse model. Mice were treated in six groups: control group (PBS), model group (LPS), LPS+MSC-CM (6 h) group, LPS+MSC-CM (12 h) group, LPS+MSCs (6 h) group and LPS+MSCs (12 h) group. Morphological and histological changes of mouse uterus were observed, and mouse uterine inflammation index myeloperoxidase (MPO) and related immune index TNF-alpha, IL-6 and IL-1 beta levels were detected by ELISA. Results: There exist remarkable inflammatory response and an obvious increase in the value of MPO, TNF-alpha, IL-1 beta and IL-6 in the endometritis mouse model compared with the control group. Morphological and histological appearances were relieved after treated with hUC-MSCs and MSC-CM. Besides, the value of MPO, TNF-alpha, IL-1 beta and IL-6 showed different degrees of decline. In comparison with LPS+MSC-CM (12 h) and LPS+MSCs (12 h) group, there was significant decrease in inflammatory indicators in LPS+MSC-CM (6 h) and LPS+MSCs (6 h) group. Conclusions: Intrauterine infusion of hUC-MSCs and MSC-CM can alleviate LPS induced endometritis.

Cultured meat technology is a novel and promising alternative strategy for meat production, and it provides an efficient, safe, and sustainable way to supply animal protein. Cytokines play an important role in promoting the rapid proliferation of cells, but the high cost and potential food safety concerns of commercial cytokines have hindered their application in large-scale cultured meat production. Herein, Saccharomyces cerevisiae C800 was used as a starting strain in which four cytokines were exogenously expressed simultaneously using the Cre-loxP system, including long-chain human insulin growth factor-1, platelet-derived growth factor-BB, basic fibroblast growth factor, and epidermal growth factor. Through promoter optimization, endogenous protease knockout, genomic co-expression, expression frame gene order optimization, and fermentation optimization, a recombinant strain CPK2B2 co-expressing four cytokines was obtained with a yield of 18.35 mg/L. After cell lysis and filter sterilization, the CPK2B2 lysate was directly added to the culture medium of porcine muscle satellite cells (MuSCs). CPK2B2 lysate promoted the growth of MuSCs and increased the proportion of G2/S cells and EdU+ cells significantly, indicating its efficacy in promoting cell proliferation. This study provides a simple and cost-saving strategy by using S. cerevisiae to produce a recombinant cytokine combination for cultured meat production.

目的 检测食管鳞癌(esophageal squamous cell carcinoma,ESCC)患者外周血NK细胞、NKT细胞中Ku70 蛋白表达水平,并探索其对 ESCC的临床意义及预后价值.方法 对前期 ESCC 患者和健康人的外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)质谱结果进行生物信息学分析,筛选出差异蛋白 Ku70,流式细胞学验证 Ku70 在 NK 细胞和 NKT 细胞中的表达,分析两者的联系及临床意义.结果 蛋白质谱发现 522 个差异蛋白,其中 310 个蛋白上调,212 个蛋白下调,通过生信分析筛选出 Ku70蛋白.流式细胞术分析显示,肿瘤组的PBMCs中CD3+CD56+NKT细胞和CD16+CD56+NK细胞的Ku70 荧光强度和阳性表达率均低于健康对照组.结论 我们获得了 ESCC患者 PBMCs的差异表达蛋白谱,其中 Ku70 在 ESCC 患者 CD3+CD56+NKT 细胞和 CD16+CD56+NK细胞中表达降低显著,可能成为 ESCC外周血检测的生物标志物.