Pub Date : 2025-11-25DOI: 10.1038/s41423-025-01369-5
Emma Miglierina, Julien Bouder, Delfina Ordanoska, Maïwenn Pineau, Simon Léonard, Anaïs Schavgoulidze, Gwenaëlle Quéré, Maeva Le Goff, Maé Bouchet, Steve Alexandre Genebrier, Samuel Bastos Serra Trinca, Laurent Deleurme, Céline Monvoisin, Laure Derrier, Charles Dumontet, Laurent Delpy, Jérôme Moreaux, Jill Corre, Michel Cogné, Brice Laffleur
DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.
{"title":"DIS3 licenses B cells for plasma cell differentiation in humans","authors":"Emma Miglierina, Julien Bouder, Delfina Ordanoska, Maïwenn Pineau, Simon Léonard, Anaïs Schavgoulidze, Gwenaëlle Quéré, Maeva Le Goff, Maé Bouchet, Steve Alexandre Genebrier, Samuel Bastos Serra Trinca, Laurent Deleurme, Céline Monvoisin, Laure Derrier, Charles Dumontet, Laurent Delpy, Jérôme Moreaux, Jill Corre, Michel Cogné, Brice Laffleur","doi":"10.1038/s41423-025-01369-5","DOIUrl":"10.1038/s41423-025-01369-5","url":null,"abstract":"DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"31-47"},"PeriodicalIF":19.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01369-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1038/s41423-025-01368-6
Takashi Shimizu, Marco Prinz
Microglia, the resident immune cells of the central nervous system, exhibit conserved developmental origins and core molecular signatures across vertebrate species, highlighting their crucial importance in the central nervous system. While homeostatic microglia maintain similar functions during phylogeny—such as immune surveillance, debris clearance, and synaptic pruning—their morphology, gene expression, and responses to stimuli remarkably vary by species. These differences reflect evolutionary divergence shaped by factors such as lifespan, regenerative potential, and immune architecture. This review integrates current findings from basic vertebrates such as zebrafish, rodents, and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution. Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.
{"title":"Microglia across evolution: from conserved origins to functional divergence","authors":"Takashi Shimizu, Marco Prinz","doi":"10.1038/s41423-025-01368-6","DOIUrl":"10.1038/s41423-025-01368-6","url":null,"abstract":"Microglia, the resident immune cells of the central nervous system, exhibit conserved developmental origins and core molecular signatures across vertebrate species, highlighting their crucial importance in the central nervous system. While homeostatic microglia maintain similar functions during phylogeny—such as immune surveillance, debris clearance, and synaptic pruning—their morphology, gene expression, and responses to stimuli remarkably vary by species. These differences reflect evolutionary divergence shaped by factors such as lifespan, regenerative potential, and immune architecture. This review integrates current findings from basic vertebrates such as zebrafish, rodents, and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution. Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1533-1548"},"PeriodicalIF":19.8,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01368-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1038/s41423-025-01370-y
Alice Werynski, Chun-Xiao Li, Yujing Hao, Andrea Cerutti, Kang Chen
{"title":"Author Correction: Not marginal but central: type I interferons unleash marginal zone B cells in Sjögren’s disease","authors":"Alice Werynski, Chun-Xiao Li, Yujing Hao, Andrea Cerutti, Kang Chen","doi":"10.1038/s41423-025-01370-y","DOIUrl":"10.1038/s41423-025-01370-y","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1648-1648"},"PeriodicalIF":19.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01370-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intracerebral hemorrhage (ICH) causes hematoma formation, leading to PHE, which is associated with leukocyte mobilization and increased inflammation at the site of brain injury. However, the fate of accumulated leukocytes within the hematoma and their impact on PHE expansion remain unknown. We performed single-cell immune profiling of hematoma cells from patients with acute ICH and reported a distinct phenotypic transformation of CD8+ T cells within the hematoma during the first 24 h after onset. In addition to enhanced IFN-γ production and migration capacity, these CD8+ T cells displayed remarkable glycolytic signatures. The metabolic fitness and functional reprogramming of hematomal CD8+ T cells are associated with the transcription factor FOXO1. Single-cell profiling of brain-infiltrating CD8+ T cells within the perihematomal tissues of ICH patients and cell culture assays revealed their capacity to activate microglia via the production of IFN-γ. Furthermore, the removal of hematomal CD8+ T cells reduced neuroinflammation, PHE expansion and neurological deficits in ICH mice. Thus, CD8+ T cells undergo metabolic and functional reprogramming within the hematoma during the acute phase of ICH, which contributes to PHE formation and neurological deterioration.
{"title":"FOXO1-driven metabolic reprogramming of hematomal CD8+ T cells drives the expansion of perihematomal edema following intracerebral hemorrhage","authors":"Jie Lin, Honglei Ren, Youliang Wang, Hanzhi Yu, Zhili Chen, Xintong Yu, Zhuyu Gao, Yan Zheng, Quanhong Wu, Yizhe Zhang, Qijian Lin, Rui Li, Decai Tian, Zhigang Cai, Qiang Liu, Ying Fu","doi":"10.1038/s41423-025-01363-x","DOIUrl":"10.1038/s41423-025-01363-x","url":null,"abstract":"Intracerebral hemorrhage (ICH) causes hematoma formation, leading to PHE, which is associated with leukocyte mobilization and increased inflammation at the site of brain injury. However, the fate of accumulated leukocytes within the hematoma and their impact on PHE expansion remain unknown. We performed single-cell immune profiling of hematoma cells from patients with acute ICH and reported a distinct phenotypic transformation of CD8+ T cells within the hematoma during the first 24 h after onset. In addition to enhanced IFN-γ production and migration capacity, these CD8+ T cells displayed remarkable glycolytic signatures. The metabolic fitness and functional reprogramming of hematomal CD8+ T cells are associated with the transcription factor FOXO1. Single-cell profiling of brain-infiltrating CD8+ T cells within the perihematomal tissues of ICH patients and cell culture assays revealed their capacity to activate microglia via the production of IFN-γ. Furthermore, the removal of hematomal CD8+ T cells reduced neuroinflammation, PHE expansion and neurological deficits in ICH mice. Thus, CD8+ T cells undergo metabolic and functional reprogramming within the hematoma during the acute phase of ICH, which contributes to PHE formation and neurological deterioration.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1629-1641"},"PeriodicalIF":19.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01363-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-12DOI: 10.1038/s41423-025-01367-7
Jueun Oh, Yun-Ho Hwang, Jihye Lee, Cheong Seok, SuHyeon Oh, Hye Yoon Kim, Nabukenya Mariam, Jaeyoung Ahn, GyeongJu Yu, Jaewoo Park, Hayeon Kim, Suhyun Kim, Seyun Shin, Min-Chul Jung, Jinwoo Gil, Joo Sang Lee, Young Ki Choi, Dokeun Kim, Daesik Kim, You-Jin Kim, SangJoon Lee
Monkeypox, a zoonotic disease caused by the monkeypox virus (MPXV), has significant global public health implications. Inflammasomes serve as crucial components of the innate immune system, detecting pathogens and triggering cell death in infected cells to eliminate harmful agents. However, the precise molecular mechanisms governing the activation of inflammasomes during MPXV infection remain largely unclear. Using CRISPR-knockout cytosolic innate immune sensor screening, we identified AIM2 as the sensor for MPXV within the inflammasome, a trigger for inflammatory cell death. Mechanistically, AIM2 forms a complex with essential cell death molecules, including ASC and caspase-1 (CASP1), without interacting with RIPK3 or CASP8. Loss of ASC, CASP1, or gasdermin D (GSDMD) reduced cell death following MPXV infection, whereas loss of GSDME, CASP3, CASP6, CASP7, CASP9, RIPK3, or MLKL did not. Pyroptotic cell death was predominantly observed in infected cells, whereas apoptotic and necroptotic signaling pathways were primarily activated in uninfected bystander cells. Furthermore, we found that the transcription factor IRF1 serves as an upstream regulator of AIM2, controlling AIM2-dependent cell death. In experiments involving AIM2-deficient mice infected with MPXV, we observed a decrease in proinflammatory cytokines, multiple inflammatory cell death pathways, and leukocyte migration, culminating in increased viral spread. CAST/EiJ mice succumbed to high-dose MPXV infection within 8 days, whereas AIM2 inhibition increased survival, with 10% of the mice treated with an AIM2 inhibitor surviving the infection. In a low-dose infection model, AIM2 inhibition reduced IL-1β and IL-18 production, LDH release, and tissue pathology. These findings highlight the critical role of AIM2-mediated inflammasome activation, along with multiple programmed cell death pathways, in shaping the innate immune response to MPXV infection, offering valuable insights for developing therapeutic strategies targeting AIM2 and the broader innate immune response against monkeypox.
猴痘是由猴痘病毒（MPXV）引起的人畜共患疾病，具有重大的全球公共卫生影响。炎性小体是先天免疫系统的重要组成部分，检测病原体并触发感染细胞死亡以消除有害物质。然而，MPXV感染过程中控制炎症小体激活的精确分子机制在很大程度上仍不清楚。通过crispr敲除细胞质先天免疫传感器筛选，我们确定AIM2是炎症小体中MPXV的传感器，这是炎症细胞死亡的触发因素。在机制上，AIM2与必需的细胞死亡分子，包括ASC和caspase-1 （CASP1）形成复合物，而不与RIPK3或CASP8相互作用。ASC、CASP1或gasdermin D （GSDMD）的缺失减少了MPXV感染后的细胞死亡，而GSDME、CASP3、CASP6、CASP7、CASP9、RIPK3或MLKL的缺失则没有这种作用。在感染细胞中主要观察到焦亡细胞死亡，而凋亡和坏死信号通路主要在未感染的旁观者细胞中激活。此外，我们发现转录因子IRF1作为AIM2的上游调节因子，控制AIM2依赖性细胞死亡。在涉及感染MPXV的aim2缺陷小鼠的实验中，我们观察到促炎细胞因子减少，多种炎症细胞死亡途径和白细胞迁移，最终导致病毒传播增加。CAST/EiJ小鼠在8天内死于高剂量MPXV感染，而AIM2抑制提高了存活率，用AIM2抑制剂治疗的小鼠中有10%存活。在低剂量感染模型中，AIM2抑制降低了IL-1β和IL-18的产生、LDH释放和组织病理。这些发现强调了AIM2介导的炎性小体激活的关键作用，以及多种程序性细胞死亡途径，在形成MPXV感染的先天免疫反应中，为开发针对AIM2和更广泛的猴痘先天免疫反应的治疗策略提供了有价值的见解。
{"title":"AIM2 drives inflammatory cell death and monkeypox pathogenesis","authors":"Jueun Oh, Yun-Ho Hwang, Jihye Lee, Cheong Seok, SuHyeon Oh, Hye Yoon Kim, Nabukenya Mariam, Jaeyoung Ahn, GyeongJu Yu, Jaewoo Park, Hayeon Kim, Suhyun Kim, Seyun Shin, Min-Chul Jung, Jinwoo Gil, Joo Sang Lee, Young Ki Choi, Dokeun Kim, Daesik Kim, You-Jin Kim, SangJoon Lee","doi":"10.1038/s41423-025-01367-7","DOIUrl":"10.1038/s41423-025-01367-7","url":null,"abstract":"Monkeypox, a zoonotic disease caused by the monkeypox virus (MPXV), has significant global public health implications. Inflammasomes serve as crucial components of the innate immune system, detecting pathogens and triggering cell death in infected cells to eliminate harmful agents. However, the precise molecular mechanisms governing the activation of inflammasomes during MPXV infection remain largely unclear. Using CRISPR-knockout cytosolic innate immune sensor screening, we identified AIM2 as the sensor for MPXV within the inflammasome, a trigger for inflammatory cell death. Mechanistically, AIM2 forms a complex with essential cell death molecules, including ASC and caspase-1 (CASP1), without interacting with RIPK3 or CASP8. Loss of ASC, CASP1, or gasdermin D (GSDMD) reduced cell death following MPXV infection, whereas loss of GSDME, CASP3, CASP6, CASP7, CASP9, RIPK3, or MLKL did not. Pyroptotic cell death was predominantly observed in infected cells, whereas apoptotic and necroptotic signaling pathways were primarily activated in uninfected bystander cells. Furthermore, we found that the transcription factor IRF1 serves as an upstream regulator of AIM2, controlling AIM2-dependent cell death. In experiments involving AIM2-deficient mice infected with MPXV, we observed a decrease in proinflammatory cytokines, multiple inflammatory cell death pathways, and leukocyte migration, culminating in increased viral spread. CAST/EiJ mice succumbed to high-dose MPXV infection within 8 days, whereas AIM2 inhibition increased survival, with 10% of the mice treated with an AIM2 inhibitor surviving the infection. In a low-dose infection model, AIM2 inhibition reduced IL-1β and IL-18 production, LDH release, and tissue pathology. These findings highlight the critical role of AIM2-mediated inflammasome activation, along with multiple programmed cell death pathways, in shaping the innate immune response to MPXV infection, offering valuable insights for developing therapeutic strategies targeting AIM2 and the broader innate immune response against monkeypox.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1615-1628"},"PeriodicalIF":19.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01367-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells. It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs. Here, we demonstrate that mature low-density neutrophils in colorectal cancer patients abnormally accumulate neutral lipids and induce the reactivation of dormant tumor cells, a process regulated by hepatic stellate cells. Mechanistically, activated hepatic stellate cells increased DGAT1/2-dependent lipid droplet synthesis in low-density neutrophils through the secretion of IL33, thereby maintaining the survival and immunosuppressive function of these neutrophils. The uptake of lipids from lipid-laden low-density neutrophils drives dormant tumor cell reactivation through the potentiation of β-oxidation and the stimulation of protumorigenic eicosanoid synthesis. In mouse models, targeting IL33 blocked neutrophil lipid synthesis, decreased the colonization of colorectal cancer cells in the liver, and enhanced the efficacy of immunotherapy. Overall, our study revealed that lipid accumulation in mature low-density neutrophils regulates the growth of dormant tumor cells and antitumor immunity to facilitate colorectal cancer liver metastasis. Targeting IL33 could be a promising therapeutic approach for colorectal cancer liver metastases.
{"title":"IL33-induced lipid droplet formation in mature low-density neutrophils drives colorectal cancer liver metastasis","authors":"Yuchen Zhang, Suyue Yu, Dina Yeernuer, Wangyi Liu, Zhuoqing Xu, Wenqing Feng, Zeping Lv, Xuanhao Liu, Peiqi Tan, Minhua Zheng, Yaping Zong, Aiguo Lu, Jingkun Zhao","doi":"10.1038/s41423-025-01365-9","DOIUrl":"10.1038/s41423-025-01365-9","url":null,"abstract":"The microenvironment of distant organs affects the colonization and growth of disseminated tumor cells. It remains unclear how tumor-associated neutrophils are influenced by the microenvironment of distant organs. Here, we demonstrate that mature low-density neutrophils in colorectal cancer patients abnormally accumulate neutral lipids and induce the reactivation of dormant tumor cells, a process regulated by hepatic stellate cells. Mechanistically, activated hepatic stellate cells increased DGAT1/2-dependent lipid droplet synthesis in low-density neutrophils through the secretion of IL33, thereby maintaining the survival and immunosuppressive function of these neutrophils. The uptake of lipids from lipid-laden low-density neutrophils drives dormant tumor cell reactivation through the potentiation of β-oxidation and the stimulation of protumorigenic eicosanoid synthesis. In mouse models, targeting IL33 blocked neutrophil lipid synthesis, decreased the colonization of colorectal cancer cells in the liver, and enhanced the efficacy of immunotherapy. Overall, our study revealed that lipid accumulation in mature low-density neutrophils regulates the growth of dormant tumor cells and antitumor immunity to facilitate colorectal cancer liver metastasis. Targeting IL33 could be a promising therapeutic approach for colorectal cancer liver metastases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1598-1614"},"PeriodicalIF":19.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01365-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although radiotherapy (RT) plays a crucial role in the local treatment of hepatocellular carcinoma, its therapeutic efficacy is often hindered by radiation resistance, the mechanisms of which remain poorly understood. Single-cell and bulk RNA sequencing analyses identified the DNA damage repair gene mortality factor 4-like 1 (MORF4L1) as a critical regulator of hepatocellular carcinoma progression and resistance to RT. This finding was further validated using clinical cohorts, patient-derived xenograft models, and in vitro experiments. Immunoprecipitation followed by mass spectrometry analysis revealed that partner and localiser of BRCA2 is an interaction partner of MORF4L1. Furthermore, MORF4L1 was demonstrated to acetylate partner and localiser of BRCA2 at lysine 628, inhibiting its ubiquitination and subsequent degradation. Additionally, MORF4L1 enhanced histone H3 acetylation at lysine 4, which facilitates DNA damage repair factor recruitment. Cross-priming assay and genetically engineered mouse model results indicated that MORF4L1 antagonist argatroban in combination with RT enhances anti-tumor immune responses by activating the cyclic GMP-AMP synthase–stimulator of interferon genes signaling pathway. This combination significantly improved the therapeutic efficacy of RT when used alongside immune checkpoint inhibitors. The study findings underscore the pivotal role of MORF4L1 in hepatocellular carcinoma progression and RT resistance, suggesting that combining argatroban with RT may overcome RT resistance and improve therapeutic outcomes.
{"title":"Targeting MORF4L1-mediated DNA repair potentiates RT-induced antitumor immunity via cGAS-STING activation in hepatocellular carcinoma","authors":"Si-Wei Wang, Wei-Feng Hong, Yi-Lan Huang, Yi-Min Zheng, Qiu-Yi Zheng, Jun-Jie Cheng, Bu-Fu Tang, Gen-Wen Chen, Bu-Gang Liang, Jia-Cheng Lu, Li Yuan, Shu-Jung Hsu, Yang Zhang, Xiao-Bin Zheng, Zhao-Chong Zeng, Jian Zhou, Jia Fan, Ai-Wu Ke, Chao Gao, Shi-Suo Du","doi":"10.1038/s41423-025-01351-1","DOIUrl":"10.1038/s41423-025-01351-1","url":null,"abstract":"Although radiotherapy (RT) plays a crucial role in the local treatment of hepatocellular carcinoma, its therapeutic efficacy is often hindered by radiation resistance, the mechanisms of which remain poorly understood. Single-cell and bulk RNA sequencing analyses identified the DNA damage repair gene mortality factor 4-like 1 (MORF4L1) as a critical regulator of hepatocellular carcinoma progression and resistance to RT. This finding was further validated using clinical cohorts, patient-derived xenograft models, and in vitro experiments. Immunoprecipitation followed by mass spectrometry analysis revealed that partner and localiser of BRCA2 is an interaction partner of MORF4L1. Furthermore, MORF4L1 was demonstrated to acetylate partner and localiser of BRCA2 at lysine 628, inhibiting its ubiquitination and subsequent degradation. Additionally, MORF4L1 enhanced histone H3 acetylation at lysine 4, which facilitates DNA damage repair factor recruitment. Cross-priming assay and genetically engineered mouse model results indicated that MORF4L1 antagonist argatroban in combination with RT enhances anti-tumor immune responses by activating the cyclic GMP-AMP synthase–stimulator of interferon genes signaling pathway. This combination significantly improved the therapeutic efficacy of RT when used alongside immune checkpoint inhibitors. The study findings underscore the pivotal role of MORF4L1 in hepatocellular carcinoma progression and RT resistance, suggesting that combining argatroban with RT may overcome RT resistance and improve therapeutic outcomes.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1549-1566"},"PeriodicalIF":19.8,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-29DOI: 10.1038/s41423-025-01361-z
Ai Li, Dengfeng Kang, Zhongsheng Feng, Haifeng Lian, Xiang Gao, Xiaohan Wu, Han Gao, Xiaoyu Li, Fushun Kou, Jian Lin, Jinghan Hua, Long Ju, Zixuan Xu, Pingchang Yang, Xue Li, Zhanju Liu
YdjC chitooligosaccharide deacetylase homolog (YDJC) has been identified as a susceptibility gene for inflammatory bowel disease (IBD), yet its role in the pathogenesis of IBD, particularly in regulating immune responses in the gut mucosa, remains elusive. In this study, we demonstrated that YDJC expression is downregulated in inflamed mucosa, particularly in the CD4+ T cells of IBD patients, and that Ydjc deficiency promotes CD4+ T-cell proliferation and Th1 cell differentiation, thereby exacerbating acute and chronic colitis in mice. Integrative transcriptomic, proteomic, and metabolomic analyses revealed that Ydjc-/-CD4+ T cells exhibit upregulated SREBP2-mediated cholesterol biosynthesis. Consistently, treatment with key enzyme inhibitors targeting cholesterol biosynthesis, including simvastatin, fatostatin, and AAV-sh-Srebf2, markedly suppressed CD4+ T-cell proliferation and Th1 cell differentiation, thereby alleviating colitis in Ydjc-/- mice. Mechanistically, YDJC directly deacetylates SREBP2, which further suppresses downstream target gene expression (e.g., Hmgcr, Hmgcs1, and Cyp51). Therefore, our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation, suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.
{"title":"YDJC restrains Th1 cell differentiation by blocking SREBP2-mediated cholesterol biosynthesis to alleviate mucosal inflammation in inflammatory bowel disease","authors":"Ai Li, Dengfeng Kang, Zhongsheng Feng, Haifeng Lian, Xiang Gao, Xiaohan Wu, Han Gao, Xiaoyu Li, Fushun Kou, Jian Lin, Jinghan Hua, Long Ju, Zixuan Xu, Pingchang Yang, Xue Li, Zhanju Liu","doi":"10.1038/s41423-025-01361-z","DOIUrl":"10.1038/s41423-025-01361-z","url":null,"abstract":"YdjC chitooligosaccharide deacetylase homolog (YDJC) has been identified as a susceptibility gene for inflammatory bowel disease (IBD), yet its role in the pathogenesis of IBD, particularly in regulating immune responses in the gut mucosa, remains elusive. In this study, we demonstrated that YDJC expression is downregulated in inflamed mucosa, particularly in the CD4+ T cells of IBD patients, and that Ydjc deficiency promotes CD4+ T-cell proliferation and Th1 cell differentiation, thereby exacerbating acute and chronic colitis in mice. Integrative transcriptomic, proteomic, and metabolomic analyses revealed that Ydjc-/-CD4+ T cells exhibit upregulated SREBP2-mediated cholesterol biosynthesis. Consistently, treatment with key enzyme inhibitors targeting cholesterol biosynthesis, including simvastatin, fatostatin, and AAV-sh-Srebf2, markedly suppressed CD4+ T-cell proliferation and Th1 cell differentiation, thereby alleviating colitis in Ydjc-/- mice. Mechanistically, YDJC directly deacetylates SREBP2, which further suppresses downstream target gene expression (e.g., Hmgcr, Hmgcs1, and Cyp51). Therefore, our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation, suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"15-30"},"PeriodicalIF":19.8,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-27DOI: 10.1038/s41423-025-01353-z
Alice Werynski, Chun-Xiao Li, Yujing Hao, Andrea Cerutti, Kang Chen
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