Molecular Medicine最新文献

{"title":"CD248 expression in human adipose tissue is upregulated in obesity and following glucocorticoid exposure: a mediator of insulin resistance and adipose dysfunction?","authors":"Rutger Laterveer, Martin H Lundqvist, Edward M Conway, Afshan N Malik, Maria K Svensson, Magnus Sundbom, Petros Katsogiannos, Jan W Eriksson, Maria J Pereira","doi":"10.1186/s10020-026-01661-8","DOIUrl":"10.1186/s10020-026-01661-8","url":null,"abstract":"<p><strong>Background: </strong>CD248 is a transmembrane glycoprotein implicated in fibrosis, hypoxia, and insulin resistance, but its role in human adipose tissue remains incompletely understood. Because glucocorticoids regulate these processes, we investigated whether CD248 is glucocorticoid responsive and characterized its expression across adipose depots and sexes in obesity.</p><p><strong>Methods: </strong>CD248 expression was assessed in adipose tissue obtained by needle biopsy (75 male/114 female, BMI: 20.1-47.9 kg/m²) and surgical sampling (24 male/39 female, BMI: 20.0-54.4 kg/m²) from individuals without type 2 diabetes, and in an additional cohort with type 2 diabetes (21 male/33 female, BMI: 22.4-42.4 kg/m²). Adipose tissue, isolated adipocytes and stromal vascular fraction were exposed to cortisol and dexamethasone. Circulating CD248 was analyzed in 44,545 participants from the UK Biobank Pharma Proteomics Project.</p><p><strong>Results: </strong>CD248 expression was higher in subcutaneous adipose tissue in obesity at mRNA (86%) and protein (2-fold) levels, with BMI as the strongest independent predictor. Expression did not differ between individuals with and without type 2 diabetes. Depot-specific differences were identified, with lower CD248 expression in omental adipose tissue than subcutaneous adipose tissue and opposing BMI associations. Sex-specific differences were observed at the protein level, with higher CD248 abundance in females with obesity. Transcriptomic analysis identified remodelling-related pathways in subcutaneous adipose tissue and metabolic pathways in omental adipose tissue. Dexamethasone and cortisol increased CD248 gene expression, and dexamethasone increased CD248 unglycosylated protein in adipocytes. Circulating CD248 increased with BMI and was higher in females with obesity, mirroring adipose tissue protein.</p><p><strong>Conclusion: </strong>Our findings identify CD248 as a glucocorticoid-responsive and depot-specific marker associated with adiposity and metabolic disturbances, suggesting a potential role in obesity-related adipose tissue dysfunction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRIP1, a G-quadruplex DNA helicase, protects against AID-induced genomic instability by limiting R-loop accumulation.","authors":"Aisha Mahboob, Haleema Ahmad, Nishat Fatma, Nasim A Begum, Afzal Husain","doi":"10.1186/s10020-026-01627-w","DOIUrl":"https://doi.org/10.1186/s10020-026-01627-w","url":null,"abstract":"<p><strong>Background: </strong>BRIP1 (BRCA1-interacting protein 1) or FANCJ is a 5'-3' DNA helicase that plays critical roles in the maintenance of genome stability through its involvement in DNA repair, replication stress responses, and the resolution of DNA secondary structures or non-B DNAs. Defects in the BRIP1 helicase gene are associated with an increased risk of various cancers. It has been shown that BRIP1-deficient mice are predisposed to B-cell lymphoma. Because activation-induced cytidine deaminase (AID)-dependent genomic instability resulting from its mistargeting to non-immunoglobulin genes is a major hallmark of B-cell lymphoma, and non-B DNA structures, including G-quadruplexes (G4) and RNA-DNA hybrids (R-loops), are implicated in AID-induced genomic instability, we asked whether BRIP1 helicase limits these secondary structures to suppress AID-mediated oncogenesis.</p><p><strong>Methods: </strong>We knocked down (KD) BRIP1 in the CH12F3-2A mouse B-cell, a model cell line for studying AID-induced physiological and non-physiological events and their underlying mechanisms. We also used biophysical assays and in silico tools to study non-B DNAs at human AID off-target sites.</p><p><strong>Results: </strong>Here, we report that BRIP1 KD increased the frequency of AID-induced events, including IgM-to-IgA antibody switching, somatic hypermutation (SHM), DNA double-strand breaks (DSBs), and IgH/c-Myc chromosomal translocations. However, BRIP1 KD does not affect either the end-joining of AID-induced DNA breaks or the synapsis of switch regions. Importantly, BRIP1 KD resulted in the accumulation of R-loops at both AID targets and off-targets. Furthermore, in silico analysis revealed G4s as the most prevalent form of non-B DNA conformation at AID off-target sites in human. We propose that BRIP1 suppresses AID-induced genomic instability by resolving non-B DNA, thereby potentially limiting the accumulation of genomic lesions that contribute to B-cell lymphoma.</p><p><strong>Conclusion: </strong>These findings revealed that BRIP1 prevents the excessive accumulation of non-B DNAs at AID target sites and suppresses AID-mediated genomic instability. These data also provide a possible explanation for why BRIP1-deficient mice are predisposed to B-cell lymphoma.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protein kinase IKK epsilon shapes the melanoma tumor microenvironment by modulating angiogenesis and the T-cell immunity.","authors":"Michelle Haß, Eleonora Mungo, Denis Benning, Andreas Weigert, Blerina Aliraj, Josefine Jakob, Björn Häupl, Thomas Oellerich, Nicole Ziegler, Aimo Kannt, Gerd Geisslinger, Ellen Niederberger","doi":"10.1186/s10020-026-01651-w","DOIUrl":"10.1186/s10020-026-01651-w","url":null,"abstract":"<p><strong>Background: </strong>Inhibitor of nuclear factor kappa-B kinase epsilon (IKKε) contributes to tumorigenesis and metastasis in various cancers. In melanoma, it is overexpressed and constitutively active. Inhibition of IKKε by either knockdown or pharmaceutical compounds reduce tumor progression by suppressing key molecular pathways within melanoma tumor cells. However, within the tumor microenvironment (TME), the role of this protein remains to be fully elucidated.</p><p><strong>Methods: </strong>Multiplex immunohistochemistry was performed on human primary melanomas to assess IKKε expression in tumor and immune cell compartments. In the mouse model, B16BL6 melanoma cells were injected subcutaneously into the flanks of wildtype and IKKε-deficient mice, and tumor growth was monitored over time. Flow-cytometric analyses characterized intratumoral immune cell populations in both genotypes, followed by in vivo CD8⁺ T-cell depletion to determine their contribution to tumor control. To elucidate molecular mechanisms underlying the differential tumor growth, we conducted targeted and untargeted proteomic analyses, which indicated regulation of angiogenic pathways which were further examined by assessing specific protein changes in tumor tissue and performing in vitro angiogenesis assays.</p><p><strong>Results: </strong>The reduced tumor growth observed in IKKε knock-out (KO) mice was concomitant with elevated levels of cytotoxic CD8⁺ and γδ-T-cells, and a diminished presence of neutrophils. Furthermore, our data revealed that isolated CD8⁺ T-cells from IKKε KO mice exhibited a higher activity in comparison to their wildtype counterparts. In addition, the depletion of CD8⁺ cells reversed the antitumor efficacy of IKKε depletion. Proteomic analysis of tumor lysates revealed a reduction of several chemokines in IKKε KO mice compared to wildtype controls, that might contribute to the reduced tumor growth and suggested that an inhibition of angiogenesis may support the antitumor activity in IKKε KO mice. This hypothesis could be confirmed by further protein analyses and angiogenesis assays.</p><p><strong>Conclusions: </strong>Our data imply that IKKε expression in melanoma is not only important in the tumor cells but also in the tumor microenvironment by regulation of the immune response and angiogenesis. Consequently, inhibition of IKKε may offer a novel therapeutic approach for melanoma, complementing existing therapies that target pathways within tumor cells and antitumor immune responses in the tumor microenvironment.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary collagen type I degradation products as common fibrosis biomarkers in chronic diseases.","authors":"Ioanna K Mina, Yaqza Hussain, Justyna Siwy, Lorenzo Catanese, Harald Rupprecht, Joachim Beige, Jan A Staessen, Jochen Metzger, Frederik Persson, Peter Rossing, Christian Delles, Joost P Schanstra, Ayman Bannaga, Antonia Vlahou, Harald Mischak, Ramesh P Arasaradnam, Agnieszka Latosinska","doi":"10.1186/s10020-026-01648-5","DOIUrl":"10.1186/s10020-026-01648-5","url":null,"abstract":"<p><strong>Background: </strong>Fibrosis, characterised by excessive accumulation of collagen type I (COL1), is a common feature of chronic diseases, including liver diseases (LDs), chronic kidney disease (CKD) and heart failure (HF). COL1 degradation products can be detected in urine by proteomics/ peptidomics analyses and may serve as non-invasive biomarkers of fibrosis. We aimed to identify a common molecular signature of fibrosis across these diseases that may ultimately guide interventions to slow disease progression and prevent organ damage.</p><p><strong>Methods: </strong>Using capillary electrophoresis coupled to mass spectrometry (CE-MS), naturally occurring COL1 degradation products (peptides) in the urine of patients with fibrotic disease, LDs (n = 127), CKD (n = 263) or HF (n = 187), were investigated and compared with the same number of matched controls. Disease-associated COL1 peptides were identified separately for each condition, and peptides showing consistent associations across the three diseases were selected to define a common fibrosis signature. A support vector machine model based on the selected peptides was developed and validated in independent cohorts of patients with LDs (n = 110), CKD (n = 93), HF (n = 32) and controls (n = 643).</p><p><strong>Results: </strong>We identified a common fibrotic signature consisting of 50 COL1 degradation products, mainly downregulated in fibrosis. A model based on these peptides achieved a strong performance, with an area under the receiver operating characteristic curve (AUC) of 0.935 (95% confidence interval (CI) 0.917-0.953, p < 0.0001) in an external validation cohort comprising pooled disease groups (LDs, CKD, and HF) and controls. Performance was maintained in LDs, CKD and HF, with AUCs of 0.917 (95% CI 0.890-0.944, p < 0.0001), 0.951 (95% CI 0.931-0.971, p < 0.0001) and 0.950 (95% CI 0.903-0.997, p < 0.0001), respectively. The model scores were significantly associated with fibrosis stage in LDs (p = 0.0097) and with interstitial fibrosis and tubular atrophy in CKD (p = 0.045).</p><p><strong>Conclusion: </strong>A model of urinary COL1 peptides captures a shared collagen degradation signature across organs and diseases, enabling the non-invasive assessment of fibrosis irrespective of its origin. As these peptides exclusively reflect collagen degradation, the findings suggest impaired collagen degradation as a driver in fibrosis. Future clinical studies are warranted to evaluate the utility of this model for early fibrosis detection and earlier implementation of anti-fibrotic interventions.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteogenomic Analysis of HDAC4 and HDAC5 in Uveal Melanoma.","authors":"Svenja Henning, Tanja J Kutzner, Martin Schneider, Teresa González-Gimeno, Yue Zheng, Utta Berchner-Pfannschmidt, Dominic Helm, Bernd Giebel, Nikolaos E Bechrakis, Samuel Peña-Llopis","doi":"10.1186/s10020-026-01652-9","DOIUrl":"10.1186/s10020-026-01652-9","url":null,"abstract":"<p><p>Uveal melanoma (UM) is a rare but aggressive cancer arising from cells of the uveal tract that is highly resistant to therapy once it has metastasized. In drug screening experiments, we identified a high sensitivity of primary UM cell lines to the pan-histone deacetylase (HDAC) inhibitor panobinostat and addressed the question whether two class IIa HDACs, HDAC4 and HDAC5, could serve as potential therapeutic targets in UM. Selective pharmacological inhibition of HDAC4/5, as well as stable knockdown of HDAC4 or HDAC5, did not strongly affect cell viability, differentiation, apoptosis or necrosis, and did not sensitize cells to other HDAC or MEK inhibitors. Proteogenomics analysis revealed 73% concordance and only 7% discordance in the expression of transcripts and proteins. Concordance reached 92% for significant transcripts. Despite the lack of severe global gene and protein expression changes in HDAC4- or HDAC5-knockdown UM cell lines, the expression of individual cancer-related genes and signaling pathways was differently regulated following HDAC4 or HDAC5 knockdown. This was particularly evident in the NF-κB pathway, which showed decreased NF-κB p65 phosphorylation in UM cell lines with monosomy in chromosome 3 (M3) genotype and mutations in BRCA1-associated protein 1 (BAP1). In summary, our results suggest that HDAC4/5 inhibitors alone are insufficient for monotherapy in UM cells, but the identification of HDAC4/5-regulated genes involved in cancer progression provides a rationale for exploring combination strategies that include HDAC4/5 inhibition.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy.","authors":"George C Bobustuc, Joshua S Smith, Sreeram Maddipatla, Sheila Jeudy, Arati Limaye, Beth Isley, Maria-Lourdes M Caparas, Susan M Constantino, Nikita Shah, Cheryl H Baker, Kalkunte S Srivenugopal, Said Baidas, Santhi D Konduri","doi":"10.1186/s10020-026-01640-z","DOIUrl":"10.1186/s10020-026-01640-z","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dopamine alters macrophage metabolism promoting intracellular Mycobacterium tuberculosis survival.","authors":"Radheshyam Modanwal, Sharmila Talukdar, Gaurav Kumar Chaubey, Rahul Dilawari, Anupam Jain, Ashish Arora, Chaaya I Raje, Manoj Raje","doi":"10.1186/s10020-026-01647-6","DOIUrl":"https://doi.org/10.1186/s10020-026-01647-6","url":null,"abstract":"<p><strong>Background: </strong>Dopamine (DA) is thought to aggravate progress of bacterial infections and enhance risk of intracellular bacterial infection like tuberculosis (TB). Though TB patients are known to present with high dopamine levels the causal link between them has remained unexplored. Mycobacterium tuberculosis (M. tb), the causative agent of TB, requires a copious supply of iron and carbon for survival and proliferation within host cells.</p><p><strong>Methods: </strong>In vitro and in vivo administration of dopamine induced an increase of non-transferrin bound iron delivery into macrophages along with and lipid accumulation and foamy macrophage formation. The resultant intracellular milieu provided an abundant source of carbon and iron for invading M. tb pathogen. Binding of dopamine to iron was characterized by NMR spectroscopy implicating its role in intracellular trafficking. Using iron sensor M. tb strain, we observed elevated iron levels in intraphagosomal bacteria residing in dopamine treated cells while CFU analysis indicated enhanced M. tb survival and proliferation.</p><p><strong>Results: </strong>We found that DA modulates macrophage metabolism resulting in creation of iron and lipid nutrient rich intracellular micro-environment favorable for survival of M. tb.</p><p><strong>Conclusions: </strong>Survival of M. tb bacilli in dopamine treated macrophages was significantly enhanced demonstrating that dopamine leads to creation of an intracellular milieu that provides a conducive and nurturing environment for invading pathogenic bacilli.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose-dependent regulation of hepatic adipsin controls glucose uptake and tolerance.","authors":"Sujay Krishna Maity, Asmita Bhar, Abhishek Sen, Tanusree Das, Atin Sasmal, Souveek Mitra, Abhijit Chowdhury, Partha Chakrabarti","doi":"10.1186/s10020-026-01620-3","DOIUrl":"10.1186/s10020-026-01620-3","url":null,"abstract":"<p><strong>Background: </strong>Complement factor D, also known as adipsin, is produced by adipose tissue, and the liver that links metabolic regulation with innate immunity. Despite its established systemic functions, the regulation of hepatic adipsin expression and its contribution to metabolic disease remain poorly defined.</p><p><strong>Methods: </strong>Hepatic adipsin expression was examined in liver biopsies from non-diabetic individuals and patients with type 2 diabetes (T2D), in murine models of type 1 diabetes (T1D) and T2D, during the fasted-to-fed transition, and in primary hepatocytes exposed to glucose. Translational regulation was assessed by glucose stimulation and pharmacological inhibition of mTOR signaling. Hepatocyte-specific adipsin knockdown was performed using liver-targeted shRNA to determine its metabolic function.</p><p><strong>Results: </strong>We show that hepatic adipsin protein abundance is markedly increased in individuals with type 2 diabetes, and positively correlates with glycated hemoglobin, despite unchanged mRNA expression. Concordantly, hepatic adipsin protein levels were elevated in multiple murine models of hyperglycemia, including type 1 diabetes (T1D), type 2 diabetes (T2D), and following fasting-refeeding transitions. In cultured hepatocytes, glucose exposure induced a rapid, dose-dependent increase in adipsin protein without altering transcript abundance, demonstrating post-transcriptional regulation. Mechanistically, glucose stimulates adipsin translation via dephosphorylation of eukaryotic initiation factor 2α (eIF2α), and activation of the mammalian target of rapamycin, mediated by the 5' untranslated region of Adipsin mRNA.Functionally, hepatocyte-specific depletion of adipsin impaired postprandial glucose tolerance, with reduced glucose uptake and a marked downregulation of glucose transporter type 2(GLUT2).</p><p><strong>Conclusions: </strong>These findings identify hepatic adipsin as a glucose-responsive translational target that couples nutrient availability to metabolic adaptation, revealingpreviously unrecognised regulation with potential relevance to diabetes pathogenesis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HEATR1 deficiency enhanced gastric cancer cell PANoptosis to boost anti-tumor immunity.","authors":"Ya Huang, Qingcheng Xu, Meijuan Zhu, Yawei Shen, Xianwen Zhang","doi":"10.1186/s10020-026-01574-6","DOIUrl":"10.1186/s10020-026-01574-6","url":null,"abstract":"<p><strong>Background: </strong>Despite the promise of immune checkpoint inhibitors (ICIs) for gastric cancer (GC) treatment, limited cytotoxic T cell infiltration remains a major barrier to therapeutic efficacy. This study investigates whether targeting HEAT repeat containing 1 (HEATR1) can induce immunogenic PANoptosis to enhance anti-tumor immunity.</p><p><strong>Methods: </strong>Bioinformatics analysis of TCGA-STAD cohort, syngeneic mouse models, and patient-derived organoids (PDOs) were employed to assess HEATR1 function. Mechanistic studies examined STAT1/IRF1 signaling, PANoptosis markers, and dendritic cell (DC) activation. Therapeutic efficacy was evaluated in combination with anti-PD1 immunotherapy.</p><p><strong>Results: </strong>HEATR1 expression inversely correlated with CD8⁺ T cell infiltration in GC tissues and was associated with advanced tumor stage and lymph node metastasis. HEATR1 knockdown suppressed tumor growth in immunocompetent but not T cell-deficient mice, demonstrating immune-dependency. Mechanistically, HEATR1 deficiency stabilized STAT1 by inhibiting proteasome-mediated degradation, thereby sensitizing GC cells to IFN-γ-induced PANoptosis through STAT1/IRF1 signaling activation. This inflammatory cell death released damage-associated molecular patterns, which promoted DC maturation and cross-priming of CD8⁺ T cells. The resulting IFN-γ secretion established a positive feedback loop amplifying tumor cell PANoptosis. PDO models confirmed that HEATR1-silenced organoids exhibited enhanced PANoptosis and DC-mediated CD8⁺ T cell expansion. HEATR1 knockdown synergized with anti-PD1 therapy to significantly inhibit tumor progression.</p><p><strong>Conclusions: </strong>HEATR1 deficiency enhances GC cell sensitivity to IFN-γ-mediated PANoptosis via STAT1/IRF1 pathway activation, creating an immunogenic tumor microenvironment that potentiates ICI efficacy. These findings identify HEATR1 as a promising therapeutic target for improving GC immunotherapy outcomes.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research advances on CD47 in digestive system cancers: from molecular mechanisms to clinical translation.","authors":"Haolin Sun, Chenyu Wei, Jianglan Long, Xiaojia Liu, Quanfu Li, Bangwei Cao","doi":"10.1186/s10020-026-01623-0","DOIUrl":"https://doi.org/10.1186/s10020-026-01623-0","url":null,"abstract":"<p><p>CD47 is a major innate immune checkpoint molecule that interacts with signal regulatory protein α (SIRPα) to deliver a \"don't eat me\" signal and restrain macrophage-mediated phagocytosis. Accumulating evidence indicates that dysregulated CD47 expression is associated with immune escape, treatment resistance, and adverse clinicopathological features in several digestive system cancers, although the strength of these associations varies across tumor types. This narrative review provides an integrative overview of CD47 structure, ligand interactions, signaling and immune-regulatory functions, and summarizes reported expression patterns and available evidence regarding regulatory mechanisms and relevant mechanistic contexts in esophageal, gastric, colorectal, hepatocellular, pancreatic, and biliary tract cancers. We further review therapeutic strategies targeting the CD47-SIRPα axis, including anti-CD47 antibodies, SIRPα fusion proteins, bispecific antibodies, and emerging cell-based and nanotechnology-based platforms, with particular attention to recent clinical developments. Finally, we critically discuss translational challenges, including hematologic toxicity and antigen sink, assay standardization and biomarker selection, resistance mechanisms, optimization of combination regimens, and the need for prospective validation of hypothesis-generating biomarker signals. By integrating recent 2025-2026 clinical developments with mechanistic and engineering advances, including lessons from unsuccessful or discontinued clinical programs, this review provides a balanced perspective on the opportunities and remaining barriers to the clinical translation of CD47-directed therapy in digestive system cancers.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}