Fusobacterium nucleatum is a key microbial driver of colorectal cancer progression. In this study, we identified an intercellular signaling axis through which F. nucleatum remodels the immune microenvironment. Analysis of 54 clinical colorectal cancer specimens revealed that high intratumoral F. nucleatum load correlated significantly with PD-L1 upregulation in tumor-associated macrophages, diminished CD8+ T-cell cytotoxicity, and poor patient prognosis. Mechanistically, F. nucleatum infection activated NF-κB signaling in colorectal cancer cells to induce the transcription of the long noncoding RNA mitotically associated long noncoding RNA (MANCR), which was selectively packaged into exosomes via the ESCRT-III/ALIX complex and transferred to macrophages. In recipient macrophages, exosomal MANCR interacted with HNRNP U to increase PD-L1 mRNA stability, leading to sustained PD-L1 surface expression. In humanized mouse models, F. nucleatum exposure inhibited CD8+ T-cell infiltration and suppressed granzyme B activity, thereby compromising antitumor immunity and facilitating tumor proliferation and metastasis. These findings demonstrate that F. nucleatum exploits a tumor-derived exosomal long noncoding RNA network to remotely manipulate macrophage plasticity. Therefore, targeting the F. nucleatum/MANCR/PD-L1 axis may represent a viable strategy to overcome immune resistance in the colorectal cancer microenvironment. SIGNIFICANCE:Fusobacterium nucleatum exploits tumor-derived exosomal MANCR to stabilize PD-L1 in macrophages, providing a mechanism of bacterial-driven immune evasion and a potential therapeutic target to restore antitumor immunity in colorectal cancer.

Studies have shown that M1 polarization of macrophages plays a crucial role in pathogenesis of acute pancreatitis (AP), although the underlying mechanisms remain incompletely understood. In this study, an in vivo AP model was induced in mice using caerulein or L-arginine, while an in vitro AP model was established by treating pancreatic acinar cells (PACs) with cholecystokinin (CCK). We observed a significant upregulation of SphK1/S1P in both CCK-treated PACs and the pancreatic tissue of AP mice. In contrast, inflammation and M1 macrophage polarization were markedly attenuated in SphK1-/- AP mice and upon treatment with pharmacological inhibitors targeting SphK1 or S1PR2. Similarly, M1 polarization of macrophages was notably induced by injured pancreatic acinar cells (iPACs), but this effect was suppressed by SphK1 knockdown or inhibition. Mechanistically, S1P derived from iPACs specifically bound to S1PR2 on macrophages, activating PI3K/JNK and ERK pathways to induce M1 polarization. Moreover, TNF-α secreted by M1 macrophages enhanced SphK1 transcription in PACs through NF-κB activation, forming a positive feedback loop between iPACs and macrophage M1 polarization. Collectively, our findings reveal that the SphK1/S1P/S1PR2/TNF-α axis mediates a reciprocal interaction between iPACs and M1 macrophages, which significantly contributes to AP pathogenesis.

Loss of immune homeostasis in Type 1 diabetes (T1D) leads to a dysregulated and autoreactive immune response that destroys pancreatic β cells, causing absolute insulin deficiency. Nevertheless, current strategies for restoring immune homeostasis remain limited. Inspired by our earlier research, we leveraged the single-cell RNA sequencing data from T1D patients, and unexpectedly found that STAT1 overrepresentation is much more prominent in dendritic cells (DCs) rather in CD4 T cells. Subsequently, we repurposed the clinically-applied STAT1 inhibitor fludarabine in T1D setting. To resolve the underlying mechanism, we employed a multipronged approach in animal studies, incorporating FACS, RNA-seq, ChIP-qPCR, Co-IP/MS, CESTA, TEM, Seahorse assay and Conditional gene knockout model. Furthermore, we investigated the significance of our data in human autoimmune diabetes. Other than directly targeting CD4+ effector T cells, fludarabine also elevated regulatory T cell (Treg) frequency, and therefore, its administration markedly alleviated T1D pathogenesis. Interestingly, fludarabine did not show a direct effect on Treg cells but indirectly fosters Treg program via inducing tolerogenic DCs (tolDCs). The fludarabine-reprogrammed tolDCs are featured by the metabolic shift towards mitochondrial oxidative respiration and exert protective effects on the adoptive transfer studies. Since the emergence of tolDCs could not be fully explained by STAT1 itself, we further explored whether fludarabine alters the STAT1 interactome. Notably, fludarabine binds to STAT1 and disrupts its interaction with the aryl hydrocarbon receptor (AhR), thereby facilitating AhR nuclear translocation. Activated AhR transcriptionally upregulated the expression of anti-inflammatory, anti-ferroptotic, and mitochondrial respiration genes to uphold the tolerogenic DC phenotype. Our findings identified that fludarabine could be a promising immunometabolic therapeutic candidate to restore immune tolerance, which may be a viable approach against T1D in clinical settings.

Lactate reshapes the tumor microenvironment (TME) through complex communication between cancer and stromal cells. However, it remains undefined whether lactate mediates the interaction between pancreatic cancer (PC) cells and pancreatic stellate cells (PSCs), a significant TME component driving tumorigenesis. This study elucidates the metabolic crosstalk between PC cells and PSCs underlying lactate-driven tumor progression. Our findings demonstrate that PC cells serve as the primary lactate source in the TME, where lactate induces PSC activation through an autophagy-dependent mechanism mediated by protein lactylation. This activation cascade subsequently upregulates programmed cell death-1 (PD-1) expression in CD8+ T cells, promoting immune evasion. Notably, AZD3965, a specific MCT1 inhibitor, sensitizes orthotopic PC to PD-1 blockade, effectively inhibiting tumor development. Mechanistically, MCT1-mediated lactate influx activates PSCs by inducing lactylation of lysine residues K356 and K781 on Vps34, a key autophagy regulator. Moreover, activated PSCs secrete CXCL9/CXCL10, which upregulates PD-1 expression in CD8+ T cells via the CXCR3/STAT3 pathway. This study establishes lactate as a crucial TME signaling molecule orchestrating PSC activation and an immunosuppressive microenvironment, providing compelling evidence for combining MCT1 inhibition with immune checkpoint blockade for pancreatic cancer.

T cell engager (TCE) therapies targeting specific tumor associated antigens (TAAs) have shown clinical efficacy in multiple types of solid tumors. Indeed, TCE has been approved to treat melanoma and small cell lung cancer. Nevertheless, it remains necessary and challenging to improve the efficacy and safety profile of TCE to deliver benefits to more cancer patients. Recurrent and chemotherapy resistant ovarian cancer remains an urgent global unmet medical need. These is limited therapeutic options for this highly lethal and refractory disease. Recently, a MUC16 TCE demonstrated promising and durable clinical efficacy against heavily pretreated MUC16-high ovarian cancer, with acceptable safety profile. This underlines the potential to develop a MUC16 TCE with favorable safety profile and enhanced anti-tumor efficacy to possibly expand the benefits to MUC16-medium and MUC16-low ovarian cancer patients. MUC16 is a glycoprotein overexpressed in several types of solid tumors, especially in the majority of ovarian cancer. Here, we developed a 2+1 format MUC16 TCE, with improved tumor cell binding affinity, enhanced tumor cell killing potency, and MUC16-dependent T cell binding and activation. This MUC16 TCE targets membrane-proximal domains of MUC16 and achieves avidity-driven tumor cell binding in the presence of soluble CA125. Moreover, this MUC16 TCE elicited limited T cell binding and activation in the absence of MUC16, compared to benchmark molecule, to minimize off-target activity. This 2+1 format MUC16 TCE also showed favorable pharmacokinetics profile in mice. Functionally, systemic administration of this MUC16 TCE showed superior anti-tumor efficacy, with undetectable toxicity, in xenograft tumor models. Importantly, this MUC16 TCE demonstrated potent and synergistic anti-tumor efficacy in combination with clinically validated therapeutic strategies for ovarian cancer in pre-clinical tumor models. This provides rationale to develop combination therapies in future clinical trials. Indeed, combination of TCE with other therapies, e.g. ADC, chemotherapy, PD1/PDL1 mAb, are being tested clinically. Together, our pre-clinical data demonstrated that a 2+1 MUC16 TCE elicits potent anti-tumor efficacy and minimized off-target T cell activation, with potential to deliver benefits to ovarian cancer patients and patient with other MUC16-positive cancer. Jinyang Li, Yang Li, Nan Gao, Yi Wang, Mengqiang Di, Min Wu, Yiyi Li, Ran Xue, Shiyu Hao, Weiwei Wu, Xiguang Zhang, Li Li, Shuaixiang Zhou, Huizhong Xiong. A 2+1 format MUC16 targeting T cell engager induces MUC16-dependent T cell activity and superior anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3510.

Ischemic cardiomyopathy remains a leading cause of heart failure (HF), yet its molecular mechanisms remain incompletely defined. This study aimed to identify the RNA-binding protein 25(RBM25) as a critical regulator of HF progression through MAP4K4 alternative splicing and p38 MAPK pathway activation. A left anterior descending (LAD) coronary artery ligation-induced HF model was established in Sprague-Dawley (SD) rats, with pericardial delivery of lentiviral vectors for RBM25 overexpression (OE-RBM25) or shRNA-mediated knockdown (sh-RBM25). Quantitative PCR (qPCR) experiments confirmed that overexpression of RBM25 induces exon 16 skipping in MAP4K4. Computational modeling further predicted that the resulting variant enhances binding to MAP3K1 and potentially activates the MAPK pathway. Cardiac function, infarct size, apoptosis, and molecular markers were evaluated via echocardiography, TTC staining, ELISA, qPCR, Western blot, and TUNEL assays. RBM25 overexpression significantly increased myocardial infarction area compared to the HF control group (p < 0.01), while RBM25 knockdown reduced infarct size (p < 0.01). Consistently, RBM25 overexpression upregulated pro-apoptotic markers (Caspase-3, Bax; p < 0.05) and downregulated anti-apoptotic Bcl-2 (p < 0.05), whereas RBM25 inhibition reversed these effects. Mechanistically, RBM25 induced exon 16 skipping in MAP4K4, generating a truncated isoform that activated MAPK signaling, as evidenced by increased phosphorylation of ERK (p < 0.05) and elevated downstream effectors (C-FOS, EGR1, PARP1; p < 0.05). P38 MAPK inhibition (SB203580) attenuated RBM25-mediated myocardial injury, while agonist-induced MAPK activation (Gambogic Amide) abolished the protective effects of RBM25 knockdown. These findings suggest that RBM25 exacerbates HF through MAP4K4 splicing-dependent p38 MAPK activation, highlighting its potential as a therapeutic target for ischemic cardiomyopathy.

Gestational diabetes mellitus (GDM) is a common pregnancy complication with far-reaching implications for maternal and offspring health, strongly tied to epigenetic modifications, particularly DNA methylation. However, the precise molecular mechanisms by which GDM increases long-term metabolic disease risk in offspring remain insufficiently understood. We integrated multiple publicly available whole-genome methylation datasets focusing on neonates born to mothers with GDM. Using differentially methylated positions (DMPs) identified in these datasets, we developed a machine learning model to predict GDM-associated epigenetic changes, then validated its performance in a clinical target cohort. In the public datasets, we identified DMPs corresponding to genes involved in glucose homeostasis and insulin sensitivity, with marked enrichment in insulin signaling, AMPK activation, and adipocytokine signaling pathways. The predictive model exhibited strong performance in public data (AUC = 0.89) and moderate performance in the clinical cohort (AUC = 0.82). Although CpG sites in the PPARG and INS genes displayed similar methylation trends in both datasets, the small validation cohort did not yield statistically significant differences. By integrating robust public data with a targeted validation cohort, this study provides a comprehensive epigenetic profile of GDM-exposed offspring. Owing to the limited sample size and lack of statistical significance, definitive conclusions cannot yet be drawn; however, the observed directional consistency suggests promising avenues for future research. Larger and more diverse cohorts are warranted to confirm these preliminary findings, clarify their clinical implications, and enhance early risk assessment for metabolic disorders in children born to GDM mothers.

Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), are critical effectors of the Hippo pathway, as well as other biochemical and biophysical signals. Through their interaction with DNA-binding partners, YAP/TAZ can modulate the transcription of many genes critical for organ size regulation and tissue homeostasis maintenance. Aberrant expression or activation of YAP/TAZ is implicated in the pathogenesis of many cancers and noncancerous diseases. Notably, their functional outputs demonstrate remarkable diversity, with context-dependent roles emerging across distinct disease models and tissue microenvironments. Posttranslational modifications (PTMs) exert profound impacts on the stability, subcellular localization, and function of YAP/TAZ. The canonical Hippo pathway-mediated phosphorylation and ubiquitination have been well characterized as mechanisms that downregulate YAP/TAZ stability and transcriptional activity. Recent studies have identified novel phosphorylation sites, atypical ubiquitination patterns, along with ubiquitin-like modifications, glycosylation, methylation, acetylation, and lactylation on YAP/TAZ. These PTMs exhibit dynamic regulation in response to microenvironmental stimuli, providing molecular insights into the context-dependent functional versatility of YAP/TAZ. This review systematically synthesizes current understanding of YAP/TAZ PTM networks and discusses their therapeutic implications.

Background: N 6-methyladenosine (m6A) modification plays a crucial role in various physiological processes by regulating mRNA biology. However, the exact impact of m6A modification on macrophages in adipose tissues under obese settings remains to be further elucidated. Methods: We established macrophage-specific Wtap-deficient mice to explore the effects of Wtap on obesity and metabolic disorders induced by high-fat diet (HFD) in mice. The molecular targets were explored by MeRIP-qPCR, and the metabolomic assays were performed to detect the alteration of relevant metabolites. Results: Wilms tumor 1-associated protein (WTAP), one of the m6A "writers", was downregulated in adipose tissue macrophages (ATMs) from obese individuals and negatively correlated with clinical metabolic traits. Depletion of Wtap in mouse macrophages exacerbated the metabolic consequences of high-fat diet (HFD) induced obesity. Additionally, energy expenditure and adipose beiging were considerably lower in Wtap-deficient mice in response to cold exposure. Mechanistic study revealed that WTAP-mediated m6A modification of isocitrate dehydrogenase 1 (Idh1) transcripts enhanced its stability and translation in macrophages leading to α-ketoglutarate (α-KG) production. Alpha-KG further supported alternative activation of macrophages by metabolic reprogramming. Conclusions: Our data support that Wtap modulates HFD-induced macrophages through interfering with the IDH1-α-KG axis, and highlight the importance of WTAP-mediated m6A modification in maintaining alternative macrophage activation, proposing potential targets for the regulation of obesity and related metabolic diseases.

Background: Thyroid eye disease (TED) is a sight-threatening autoimmune disease with cigarette smoking as one of the key risk factors. Cigarette smoking affects both the severity of TED and the patient's response to medication. However, the underlying pathogenic mechanisms of smoking in TED remain unclear. Methods: Orbital fibroblasts (OFs) were extracted from patients with TED and non-TED controls, and treated with cigarette smoking extract (CSE). Luminex assays and Western blots were employed to examine inflammatory status and pathological phenotypes of OFs. A specific reactive oxygen species (ROS) probe was used to evaluate oxidative stress levels. RNA-sequencing of CSE-treated OFs was used to analyze differentially expressed genes. Immunofluorescence and RNA-sequencing were used to examine the expression of receptor for advanced glycation end products (RAGE) signaling molecules in patients. Small interfering RNA sequences and a RAGE-specific inhibitor were employed to investigate the effects of RAGE blockade on cigarette smoking-related pathological phenotypes. To validate our findings in vivo, we generated an adenovirus-induced TED mouse model with exposure to cigarette smoke. Results: Exposure to CSE resulted in an inflammatory phenotype of OFs together with higher levels of oxidative stress. OFs exposed to CSE presented susceptibility to transforming growth factor-β-induced myofibroblast differentiation, and 15-D-PGJ2-induced adipocyte differentiation, indicating pro-fibrotic and pro-adipogenic phenotypes. RNA-sequencing of CSE-treated OFs revealed upregulation of RAGE signaling molecules. TED patients with smoking history also exhibited higher levels of RAGE signaling, both in the orbit and peripheral blood, compared with non-smoking patients. Enhancement of inflammatory status was associated with activation of the ROS-nuclear factor-kappa B pathway downstream of RAGE. RAGE gene interference or administration of RAGE inhibitor effectively mitigated cigarette smoking-related pathological changes in OFs. Disrupting RAGE signaling in TED mice efficiently ameliorated smoking-induced disease progression in vivo. Conclusions: Cigarette smoking-relevant TED progression was linked with RAGE signaling activation, leading to the exacerbation of orbital inflammation and tissue-remodeling, including fibrosis and adipogenesis. Our findings demonstrate that cigarette smoke exposure affects the biological characteristics of TED-derived OFs and supports RAGE as a promising therapeutic target for the management of patients with TED and smoking habits.

Objective: This subanalysis of a cross-sectional, nationwide study was conducted to assess the dietary status and the relationship between dietary and metabolic control in patients with DM in Guangdong Province. Methods: Data of 1623 residents with DM (48.2% male, average HbA1c: 7.6%, average calorie intake: 1869 kcal/day) in Guangdong aged 18-74 years were included. Participants were asked to finish the questionnaires including the information of consumption of different food components. Blood glucose, HbA1c, lipids, and uric acid were also measured. Results: Among all subjects, 55.5% had hypertension, 92.7% had dyslipidemia. And 46.6% of the subjects were with HbA1c<7%, 35.7% with blood pressure<130/80mmHg, and 7.1% met blood lipid control target. Only 1.7% of the subjects met all three above metabolic targets. The consumption of vegetables and livestock meat in urban areas was lower significantly, while the other food components were higher significantly in urban areas than those in rural areas. As shown in Table 1, the consumptions of food components were significantly different between subjects with optimal glycemic control, achieving LDL-C target, or with normal uric acid levels and those with poor metabolic control. Conclusion: The metabolic control in patients with DM in Guangdong Province was still unsatisfactory. The consumption of different food components may affect the metabolic status. Disclosure X. Chen: None. W. Jiang: None. F. Xiong: None. L. Yang: None. W. Xu: None. L. Zeng: None.

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS -induced enhancement in glycolytic capacity and the overproduction of IL -17A. Therefore, administration of GSK markedly alleviated HS -exacerbated RA progression in collageninduced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.

Clear cell renal cell carcinoma (ccRCC) is a complex disease with remarkable immune and metabolic heterogeneity. Here we perform genomic, transcriptomic, proteomic, metabolomic and spatial transcriptomic and metabolomic analyses on 100 patients with ccRCC from the Tongji Hospital RCC (TJ-RCC) cohort. Our analysis identifies four ccRCC subtypes including De-clear cell differentiated (DCCD)-ccRCC, a subtype with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, reduced metabolic activity, enhanced nutrient uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD is associated with worse outcomes and higher recurrence rate, suggesting that it cannot be cured by nephrectomy alone. Our study also suggests a treatment strategy based on subtype-specific immune cell infiltration that could guide the clinical management of ccRCC.

BJU InternationalEarly View Research Letter Microchip for detection of cell-free DNA in urine to help identify patients with bladder cancer Si-ming Lu, Si-ming Lu orcid.org/0000-0003-4041-1309 Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China Institute of Laboratory Medicine, Zhejiang University, Hangzhou, ChinaSearch for more papers by this authorYu Zhang, Yu Zhang Department of Clinical pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, ChinaSearch for more papers by this authorXiao-tian Dong, Xiao-tian Dong Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China Institute of Laboratory Medicine, Zhejiang University, Hangzhou, ChinaSearch for more papers by this authorJia-long Wang, Jia-long Wang orcid.org/0000-0002-0533-4021 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaSearch for more papers by this authorYang Li, Yang Li orcid.org/0000-0001-9539-7351 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaSearch for more papers by this authorLi-guo Liang, Corresponding Author Li-guo Liang [email protected] orcid.org/0000-0002-4943-5166 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Centre for Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China Correspondence: Li-guo Liang, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. e-mail: [email protected]Search for more papers by this author Si-ming Lu, Si-ming Lu orcid.org/0000-0003-4041-1309 Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China Institute of Laboratory Medicine, Zhejiang University, Hangzhou, ChinaSearch for more papers by this authorYu Zhang, Yu Zhang Department of Clinical pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, ChinaSearch for more papers by this authorXiao-tian Dong, Xiao-tian Dong Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China Institute of Laboratory Medicine, Zhejiang University, Hangzhou, ChinaSearch for more papers by this authorJia-long Wang, Jia-long Wang orcid.org/0000-0002-0533-4021 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaSearch for more papers by this authorYang Li, Yang Li orcid.org/0000-0001-9539-7351 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaSearch for more papers by this authorLi-guo Liang, Corresponding Author Li-guo Liang [email protected] orcid.org/0000-0002-4943-5166 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Centre for Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China Correspondence: Li-guo Liang, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. e-mail: [email protected]Search for more papers by this author First published: 30 January 2024 https://doi.org/10.1111/bju.16271Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Open Research Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Supporting Information Filename Description bju16271-sup-0001-TableS1.docxWord 2007 document , 15.3 KB Table S1. Clinical characteristics of the patients with BC and healthy controls. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1Richters A, Aben KKH, Kiemeney L. The global burden of urinary bladder cancer: an update. World J Urol 2020; 38: 1895–1904 10.1007/s00345-019-02984-4 PubMedWeb of Science®Google Scholar 2Linxweiler J, Junker K. Extracellular vesicles in urological malignancies: an update. Nat Rev Urol 2020; 17: 11–27 10.1038/s41585-019-0261-8 PubMedWeb of Science®Google Scholar 3Garcia Moreira V, Prieto Garcia B, de la Cera Martinez T, Alvarez Menendez FV. Elevated transrenal DNA (cell-free urine DNA) in patients with urinary tract infection compared to healthy controls. Clin Biochem 2009; 42: 729–731 10.1016/j.clinbiochem.2008.12.021 CASPubMedWeb of Science®Google Scholar 4Brisuda A, Pazourkova E, Soukup V et al. Urinary cell-free DNA quantification as non-invasive biomarker in patients with bladder cancer. Urol Int 2016; 96: 25–31 10.1159/000438828 CASPubMedWeb of Science®Google Scholar 5Liang L, Wang Y, Lu S et al. Microchips for detection of exfoliated tumor cells in urine for identification of bladder cancer. Anal Chim Acta 2018; 1044: 93–101 10.1016/j.aca.2018.07.044 CASPubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Background: Resistance to sorafenib remains a major challenge in the systemic therapy of liver cancer. However, the involvement of lipid metabolism-related lncRNAs in this process remains unclear. Methods: Different expression levels of lipid metabolism-related lncRNAs in HCC were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The influence of HNF4A-AS1 on sorafenib response was evaluated through analysis of public biobanks, cell cytotoxicity and colony formation assays. The effect of HNF4A-AS1 on sorafenib-induced ferroptosis was measured using lipid peroxidation, glutathione, malondialdehyde, and ROS levels. Furthermore, bioinformatic analyses and lipidomic profilingwere conducted to study HNF4A-AS1 involvement in lipid metabolic reprogramming. Mechanistic experiments, including the luciferase reporter assay, RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and RNA remaining assays, were employed to uncover the downstream targets and regulatory mechanisms of HNF4A-AS1 in sorafenib resistance in HCC. Xenograft and organoid experiments were carried out to assess the impact of HNF4A-AS1 on sorafenib response. Results: Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC. Conclusions: Our results indicated the pivotal role of lipid metabolism-related and liver-specific HNF4A-AS1 in inhibiting sorafenib resistance by promoting ferroptosis and suggesting that HNF4A-AS1 might be a potential target for HCC.

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.

The liver plays a pivotal role in the regulation of lipid and glucose metabolism. However, increased intake of nutrients, including glucose, fructose

The regulation of autoimmunity against pancreatic islet β cells for type 1 diabetes (T1D) onset is still unclear. NOD/ShiLtJ (NOD) mice are prone to the onset of autoimmune diabetes, but its congenic strain, ALR/Lt (ALR), is not. Here we show that dendritic cells (DC) in ALR mice have impaired migratory and T-cell priming capability. Genomic comparative analysis maps a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene when compared with NOD genome; meanwhile, data from knock-in models show that this ALR Myo9b allele impairs phenotypic and functional maturation of DCs, and prevents the development and progression of spontaneous autoimmune diabetes in NOD mice. In parallel, while the ALR 33-bp deletion of Myo9b is not conserved in human, we find a MYO9B R133Q polymorphism associating with increased risk of T1D and enhanced DC function in patients with T1D. Our results thus hint that alterations in Myo9b may contribute to altered DC function and autoimmune diabetes onset.

Objective: To study the epidemiological characteristics of adult diabetes, and effect of food composition on blood glucose in Guangdong Province. Methods: The data of this study were from the China DiaChronic Study. This study investigated diabetic patients in eight urban and rural centers in Guangdong Province. Questionnaire survey, physical examination and fundus photography were carried out, and blood and urine indexes were measured. All 1621 subjects were finally included. Results: (1) The prevalence rates of obesity, hypertension, hypertriglyceridemia, hyper LDL-C, were 15.8%, 37.9%, 50.5% and 79.3% respectively. The prevalence rates of diabetic nephropathy and retinopathy were 33.6% and 16.7% respectively. The treatment rate of subjects was 93.6%, and the compliance rate of HbA1c of them was 49%. (2) In all subjects, the median of total caloric intake of food was 1660 kcal/d, of which grains account for the most with 810 kcal, and milk were the least with 0 kcal. Men's caloric intake in grains, livestock meat, poultry meat and aquatic products were significantly higher than that of women, while women's caloric intake in potatoes and milk were significantly higher than that of men (P<0.05). The caloric intake of grains, vegetables and livestock meat in rural were significantly higher than that in urban, while the caloric intake of miscellaneous grains, potatoes, beans, fruits, milk, poultry meat, aquatic products, eggs and nuts in urban areas were higher than that in rural areas (P<0.05). For subjects with HbAIc<6.5%, the energy intake of vegetables, fruits, poultry meat and eggs was significantly higher than that of them with HbA1c>6.5% (P<0.05). Conclusion: Despite patients try to control blood glucose, half of them have poor blood glucose control. At present, the diet of rural residents mainly include grains, vegetables and livestock meat. Vegetables, fruits, poultry and eggs may be beneficial to blood glucose control, which needs further research to confirmation. Disclosure X.Chen: None. W.Jiang: None. F.Xiong: None. L.Yang: None. W.Xu: None. L.Zeng: None. S.Te china national diabetic chronic complications : n/a.