Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKE eRNA, or IKBKE-e). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically "cold" cancers such as prostate cancer.
{"title":"Reversing enhancer RNA-mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models.","authors":"Xiang Li,Rui Sun,Hao Li,Jacob J Orme,Xu Zhang,Yu Hou,Sean S Park,Yu Zhang,Yi He,Liguo Wang,Veronica Rodriguez-Bravo,Josep Domingo-Domenech,Shancheng Ren,Dan Xia,Guanghou Fu,Zhankui Jia,Haojie Huang","doi":"10.1172/jci190928","DOIUrl":"https://doi.org/10.1172/jci190928","url":null,"abstract":"Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKE eRNA, or IKBKE-e). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically \"cold\" cancers such as prostate cancer.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advances in cancer therapy have greatly extended patient survival but have also introduced a growing burden of cardiovascular toxicity that threatens long-term outcomes. These toxicities encompass a broad and often unpredictable range of clinical presentations, complicating oncologic care. Understanding how chemotherapy, targeted agents, and immune modulators impair cardiovascular function is essential for early detection, prevention, and management. Emerging insights into the cellular and molecular mechanisms, ranging from immune activation to transcriptional reprogramming and disrupted intercellular communication, underscore the complexity of cancer therapy-induced cardiac injury. Unraveling these mechanisms will be key to developing personalized, mechanism-based strategies that preserve cardiac function without compromising anticancer efficacy. As survivorship continues to improve, mitigating cardiotoxicity remains a critical priority for preserving both the quality and duration of life of patients.
{"title":"Caught in the crossfire: cardiac complications of cancer therapy.","authors":"Giulia Guerra,Marco Mergiotti,Hossein Ardehali,Emilio Hirsch,Alessandra Ghigo","doi":"10.1172/jci198289","DOIUrl":"https://doi.org/10.1172/jci198289","url":null,"abstract":"Advances in cancer therapy have greatly extended patient survival but have also introduced a growing burden of cardiovascular toxicity that threatens long-term outcomes. These toxicities encompass a broad and often unpredictable range of clinical presentations, complicating oncologic care. Understanding how chemotherapy, targeted agents, and immune modulators impair cardiovascular function is essential for early detection, prevention, and management. Emerging insights into the cellular and molecular mechanisms, ranging from immune activation to transcriptional reprogramming and disrupted intercellular communication, underscore the complexity of cancer therapy-induced cardiac injury. Unraveling these mechanisms will be key to developing personalized, mechanism-based strategies that preserve cardiac function without compromising anticancer efficacy. As survivorship continues to improve, mitigating cardiotoxicity remains a critical priority for preserving both the quality and duration of life of patients.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"101 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"W. Kimryn Rathmell receives the 2025 Stanley J. Korsmeyer Award.","authors":"","doi":"10.1172/jci204431","DOIUrl":"https://doi.org/10.1172/jci204431","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Madeline Niederkorn,Lavanya Bezavada,Anitria Cotton,Lance E Palmer,Lahiri Konada,Trent Hall,Vishwajeeth R Pagala,Jinbin Zhai,Zuo-Fei Yuan,Yingxue Fu,Jacob A Steele,Shilpa Narina,Andrew Schild,Chengzhou Wu,Sarah Aminov,Michael Schieber,Erin McGovern,Aaron B Taylor,Sandeep Gurbuxani,Peng Xu,Peng Ji,Laura J Janke,Anthony A High,Guolian Kang,Shondra M Pruett-Miller,Mitchell Weiss,Amit Verma,Raajit K Rampal,John D Crispino
Myelodysplastic syndromes (MDSs) are malignant hematopoietic stem and progenitor cell (HSPC) disorders that lead to ineffective blood production with poor outcomes. We previously showed that F-box only protein 11 (FBXO11) is downregulated in MDS, and here we report how this event contributes to disease progression. Integration of multiomics data revealed that the SCF-FBXO11 complex regulates spliceosome and ribosome components in a nucleophosmin 1 (NPM1)-centric network. FBXO11 facilitates the ubiquitylation of NPM1, whereby deletion of FBXO11 results in the reorganization of NPM1 and a de-repression of alternative splicing. Label-free total quantitative proteomics demonstrated that the FBXO11-NPM1 interactome was markedly downregulated in cells from patients with CD34+ MDS. In addition, we discovered that MYC was evicted from the FBXO11 promoter by TLR2 activation, revealing that it was a MYC target gene and explaining why FBXO11 expression was decreased in MDS. In MDS mouse models, genetic ablation of Fbxo11 exacerbated neutropenia concomitant with a profound decrease in NPM1 protein levels. Finally, we discovered rare mutations in FBXO11, which mapped to a previously unstudied functional intrinsically disordered region (IDR) in the N-terminus responsible for binding NPM1. These data support a model in which FBXO11 rewires RNA binding and ribosomal subnetworks through ubiquitylation of NPM1, ultimately restricting MDS progression.
{"title":"FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome.","authors":"Madeline Niederkorn,Lavanya Bezavada,Anitria Cotton,Lance E Palmer,Lahiri Konada,Trent Hall,Vishwajeeth R Pagala,Jinbin Zhai,Zuo-Fei Yuan,Yingxue Fu,Jacob A Steele,Shilpa Narina,Andrew Schild,Chengzhou Wu,Sarah Aminov,Michael Schieber,Erin McGovern,Aaron B Taylor,Sandeep Gurbuxani,Peng Xu,Peng Ji,Laura J Janke,Anthony A High,Guolian Kang,Shondra M Pruett-Miller,Mitchell Weiss,Amit Verma,Raajit K Rampal,John D Crispino","doi":"10.1172/jci193636","DOIUrl":"https://doi.org/10.1172/jci193636","url":null,"abstract":"Myelodysplastic syndromes (MDSs) are malignant hematopoietic stem and progenitor cell (HSPC) disorders that lead to ineffective blood production with poor outcomes. We previously showed that F-box only protein 11 (FBXO11) is downregulated in MDS, and here we report how this event contributes to disease progression. Integration of multiomics data revealed that the SCF-FBXO11 complex regulates spliceosome and ribosome components in a nucleophosmin 1 (NPM1)-centric network. FBXO11 facilitates the ubiquitylation of NPM1, whereby deletion of FBXO11 results in the reorganization of NPM1 and a de-repression of alternative splicing. Label-free total quantitative proteomics demonstrated that the FBXO11-NPM1 interactome was markedly downregulated in cells from patients with CD34+ MDS. In addition, we discovered that MYC was evicted from the FBXO11 promoter by TLR2 activation, revealing that it was a MYC target gene and explaining why FBXO11 expression was decreased in MDS. In MDS mouse models, genetic ablation of Fbxo11 exacerbated neutropenia concomitant with a profound decrease in NPM1 protein levels. Finally, we discovered rare mutations in FBXO11, which mapped to a previously unstudied functional intrinsically disordered region (IDR) in the N-terminus responsible for binding NPM1. These data support a model in which FBXO11 rewires RNA binding and ribosomal subnetworks through ubiquitylation of NPM1, ultimately restricting MDS progression.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziheng Zhao,Yuhong He,Yang Liu,Quying Feng,Hee Young Kim,Yu Fan,Xiaowei Guan
Drug-associated environmental cues can trigger drug-seeking behavior and precipitate relapse. In the current study, we identified that the claustrum (CL) connects the ventral tegmental area (VTA) with the medial prefrontal cortex (mPFC), forming the VTA-CL-mPFC circuit. By using methamphetamine (METH) conditioned place preference (CPP) model in male mice, we found that manipulating the VTA-CL-mPFC circuit or CL neuronal ensemble receiving projections from VTA and projecting to mPFC (VTA-CL-mPFC) could disrupt the retrieval of METH-paired context memory, resulting in the blockage of the acquisition of METH CPP in male mice. During the process, dopamine (DA) release and dopamine 1-like receptor (D1R)-mediated the activation of CL neurons were required for the retrieval of METH-induced reward memory in male mice. These findings reveal a midbrain-to-cortical circuit orchestrated by CL neurons, which plays an essential role in the retrieval of drug-paired environmental cue memory.
{"title":"A midbrain-cortical circuit mediated by claustrum neuronal ensemble orchestrates drug-paired context memory processing.","authors":"Ziheng Zhao,Yuhong He,Yang Liu,Quying Feng,Hee Young Kim,Yu Fan,Xiaowei Guan","doi":"10.1172/jci196944","DOIUrl":"https://doi.org/10.1172/jci196944","url":null,"abstract":"Drug-associated environmental cues can trigger drug-seeking behavior and precipitate relapse. In the current study, we identified that the claustrum (CL) connects the ventral tegmental area (VTA) with the medial prefrontal cortex (mPFC), forming the VTA-CL-mPFC circuit. By using methamphetamine (METH) conditioned place preference (CPP) model in male mice, we found that manipulating the VTA-CL-mPFC circuit or CL neuronal ensemble receiving projections from VTA and projecting to mPFC (VTA-CL-mPFC) could disrupt the retrieval of METH-paired context memory, resulting in the blockage of the acquisition of METH CPP in male mice. During the process, dopamine (DA) release and dopamine 1-like receptor (D1R)-mediated the activation of CL neurons were required for the retrieval of METH-induced reward memory in male mice. These findings reveal a midbrain-to-cortical circuit orchestrated by CL neurons, which plays an essential role in the retrieval of drug-paired environmental cue memory.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
You Zhi Nicholas Cheang,Wee Chee Yap,Kirsteen M Tullett,Xinlei Qian,Peck S Tan,Kiren Purushotorman,Wan Yi Tan,Yun Yan Mah,Paul Macary,Chee Wah Tan,Mireille H Lahoud,Sylvie Alonso
Short-lived, clade-specific immune responses with limited mucosal priming are limitations faced by current COVID-19 mRNA vaccines. We have developed a nasal booster vaccine candidate that induced robust, sustained, cross-clade, systemic and mucosal protective immunity. Two recombinant Clec9A-specific monoclonal antibodies fused to the Receptor Binding Domain (RBD) from Omicron XBB.1.5 and SARS-CoV-1, respectively were generated. In Comirnaty mRNA-vaccinated mice, boosting with both constructs combined (Clec9AOMNI) induced cross-clade neutralizing antibodies (nAbs) and T-cell responses that were greater in magnitude and more sustained compared to bivalent Comirnaty (BC) mRNA vaccine booster. Persistence of RBD-specific follicular helper CD4+ T cells, germinal centre B cells, and long-lived plasma cells that facilitated affinity maturation, correlated with detection of triple cross-reactive B cells binding the RBDs of SARS-CoV-2 ancestral, XBB.1.5, and SARS-CoV-1. Remarkably, intranasal boosting with Clec9AOMNI elicited robust and durable immunity across the upper and lower airways while concurrently boosting the systemic immunity to levels matching or exceeding those from systemic boosting. Correspondingly, Clec9AOMNI nasal booster conferred superior protection against SARS-CoV-2 challenge compared to BC mRNA booster, with undetectable viral titers in the respiratory tract. Hence, Clec9AOMNI is a promising nasal booster vaccine candidate that has the potential to mitigate pandemic threats from emerging sarbecoviruses.
{"title":"Intranasal DC-targeting vaccine booster elicits durable and cross-clade protective immunity against sarbecoviruses in mice.","authors":"You Zhi Nicholas Cheang,Wee Chee Yap,Kirsteen M Tullett,Xinlei Qian,Peck S Tan,Kiren Purushotorman,Wan Yi Tan,Yun Yan Mah,Paul Macary,Chee Wah Tan,Mireille H Lahoud,Sylvie Alonso","doi":"10.1172/jci195784","DOIUrl":"https://doi.org/10.1172/jci195784","url":null,"abstract":"Short-lived, clade-specific immune responses with limited mucosal priming are limitations faced by current COVID-19 mRNA vaccines. We have developed a nasal booster vaccine candidate that induced robust, sustained, cross-clade, systemic and mucosal protective immunity. Two recombinant Clec9A-specific monoclonal antibodies fused to the Receptor Binding Domain (RBD) from Omicron XBB.1.5 and SARS-CoV-1, respectively were generated. In Comirnaty mRNA-vaccinated mice, boosting with both constructs combined (Clec9AOMNI) induced cross-clade neutralizing antibodies (nAbs) and T-cell responses that were greater in magnitude and more sustained compared to bivalent Comirnaty (BC) mRNA vaccine booster. Persistence of RBD-specific follicular helper CD4+ T cells, germinal centre B cells, and long-lived plasma cells that facilitated affinity maturation, correlated with detection of triple cross-reactive B cells binding the RBDs of SARS-CoV-2 ancestral, XBB.1.5, and SARS-CoV-1. Remarkably, intranasal boosting with Clec9AOMNI elicited robust and durable immunity across the upper and lower airways while concurrently boosting the systemic immunity to levels matching or exceeding those from systemic boosting. Correspondingly, Clec9AOMNI nasal booster conferred superior protection against SARS-CoV-2 challenge compared to BC mRNA booster, with undetectable viral titers in the respiratory tract. Hence, Clec9AOMNI is a promising nasal booster vaccine candidate that has the potential to mitigate pandemic threats from emerging sarbecoviruses.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epidermal growth factor receptor (EGFR)-activating mutations are established biomarkers of resistance to immune checkpoint blockade (ICB) in lung cancer, yet the precise molecular mechanism and effective therapeutic strategies remain elusive. In this study, we show that EGFR overexpression and amplification recapitulate the negative impact of EGFR driver mutations to ICB response, indicating a proactive involvement of EGFR signaling in antagonizing antitumor immune response. Functional studies unveil that EGFR activation suppresses cellular response to interferon-gamma (IFN-γ) following ICB treatment across multiple cancer models. This impairment in IFN-γ responsiveness further limits the upregulation of T cell-recruiting chemokines and antigen presentation, resulting in reduced T cell infiltration and activation, ultimately undermining antitumor immunity. Mechanistically, EGFR promotes SHP2 activation to accelerate STAT1 dephosphorylation, leading to premature termination of the IFN-γ response. SHP2 inhibition restored ICB sensitivity in EGFR-activated tumors, significantly reducing tumor burden while maintaining a favorable safety profile. Our findings suggest that EGFR/SHP2 axis functions as a molecular brake to disrupt the initiation and amplification of IFN-γ mediated anti-tumor response during immunotherapy. This discovery unveils a potential avenue to overcome immunotherapy resistance in EGFR-driven tumors, particularly lung cancer, through SHP2-targeted combination strategies.
{"title":"EGFR activation disrupts immunotherapy response via SHP2-mediated suppression of tumor-intrinsic response to IFN-γ.","authors":"Wei-Tao Zhuang,Lan-Lan Pang,Li-Yang Hu,Jun Liao,Jian-Hua Zhan,Ting Li,Ri-Xin Chen,Jia-Ni Zheng,An-Lin Li,Wen-Yan Yu,Tian-Qin Mao,Liang Chen,Yu-Jian Huang,Shao-Dong Hong,Jing Li,Jun-Han Wu,Yi-Ming Zeng,Meng-Juan Yang,Hai-Qing Zeng,Ya-Xiong Zhang,Li Zhang,Wen-Feng Fang","doi":"10.1172/jci194377","DOIUrl":"https://doi.org/10.1172/jci194377","url":null,"abstract":"Epidermal growth factor receptor (EGFR)-activating mutations are established biomarkers of resistance to immune checkpoint blockade (ICB) in lung cancer, yet the precise molecular mechanism and effective therapeutic strategies remain elusive. In this study, we show that EGFR overexpression and amplification recapitulate the negative impact of EGFR driver mutations to ICB response, indicating a proactive involvement of EGFR signaling in antagonizing antitumor immune response. Functional studies unveil that EGFR activation suppresses cellular response to interferon-gamma (IFN-γ) following ICB treatment across multiple cancer models. This impairment in IFN-γ responsiveness further limits the upregulation of T cell-recruiting chemokines and antigen presentation, resulting in reduced T cell infiltration and activation, ultimately undermining antitumor immunity. Mechanistically, EGFR promotes SHP2 activation to accelerate STAT1 dephosphorylation, leading to premature termination of the IFN-γ response. SHP2 inhibition restored ICB sensitivity in EGFR-activated tumors, significantly reducing tumor burden while maintaining a favorable safety profile. Our findings suggest that EGFR/SHP2 axis functions as a molecular brake to disrupt the initiation and amplification of IFN-γ mediated anti-tumor response during immunotherapy. This discovery unveils a potential avenue to overcome immunotherapy resistance in EGFR-driven tumors, particularly lung cancer, through SHP2-targeted combination strategies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dysregulation of cell cycle checkpoints is a cancer hallmark with ubiquitination controlled protein stability playing pivotal roles. Although p21, a key cyclin-dependent kinase inhibitor, is tightly regulated by ubiquitin-mediated degradation, the key upstream modulators of its ubiquitination remain incompletely defined. Here, we identify poly(ADP-ribose) glycohydrolase (PARG) as a regulator of p21 stability in gastric cancer (GC) cells. We show that PARG expression is markedly upregulated in GC tissues and correlates with poor patient prognosis. Functional assays revealed that genetic depletion of PARG triggers G2/M phase arrest and impairs GC cell proliferation. Mechanistically, we demonstrate that PARG loss enhances p21 PARylation, which disrupts its association with E3 ubiquitin ligase, thereby reducing K48-linked ubiquitination and leading to p21 protein stabilization. Moreover, we identify lysine residues K161 and K163 as critical sites for PARG-mediated regulation of p21 ubiquitination. Our findings reveal a post-translational regulatory axis in which PARG governs cell cycle progression by modulating the PARylation-dependent ubiquitination of p21. These results broaden the understanding of p21 regulation in cancer and highlight PARG as a potential therapeutic target for GC treatment.
{"title":"Poly(ADP-ribose) glycohydrolase enforces p21 degradation via dePARylation to promote gastric cancer progression.","authors":"Yangchan Hu,Qimei Bao,Yixing Huang,Yan Wang,Xin Zhao,Junjun Nan,Yuxin Meng,Mingcong Deng,Yuancong Li,Zirui Zhuang,Hanyi He,Dan Zu,Yuke Zhong,Chunkai Zhang,Bing Wang,Ran Li,Yanhua He,Qihan Wang,Min Liu,John A Tainer,Yin Shi,Xiangdong Cheng,Ji Jing,Zu Ye","doi":"10.1172/jci195538","DOIUrl":"https://doi.org/10.1172/jci195538","url":null,"abstract":"Dysregulation of cell cycle checkpoints is a cancer hallmark with ubiquitination controlled protein stability playing pivotal roles. Although p21, a key cyclin-dependent kinase inhibitor, is tightly regulated by ubiquitin-mediated degradation, the key upstream modulators of its ubiquitination remain incompletely defined. Here, we identify poly(ADP-ribose) glycohydrolase (PARG) as a regulator of p21 stability in gastric cancer (GC) cells. We show that PARG expression is markedly upregulated in GC tissues and correlates with poor patient prognosis. Functional assays revealed that genetic depletion of PARG triggers G2/M phase arrest and impairs GC cell proliferation. Mechanistically, we demonstrate that PARG loss enhances p21 PARylation, which disrupts its association with E3 ubiquitin ligase, thereby reducing K48-linked ubiquitination and leading to p21 protein stabilization. Moreover, we identify lysine residues K161 and K163 as critical sites for PARG-mediated regulation of p21 ubiquitination. Our findings reveal a post-translational regulatory axis in which PARG governs cell cycle progression by modulating the PARylation-dependent ubiquitination of p21. These results broaden the understanding of p21 regulation in cancer and highlight PARG as a potential therapeutic target for GC treatment.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yasmin Zakiniaeiz,Nakul R Raval,Will Riordan,Nabeel Nabulsi,Yiyun Huang,Brian Pittman,David Matuskey,Gustavo A Angarita,Robin Bonomi,Sherry A McKee,Ansel T Hillmer,Kelly P Cosgrove
BACKGROUNDChronic alcohol use leads to synaptic dysfunction in preclinical studies. However, whether in vivo synaptic density deficits are found in people with alcohol use disorder (AUD) remains unclear.METHODSThirty-two people with AUD (17 women) and 29 controls (17 women) completed one positron emission tomography (PET) brain imaging scan with the radiotracer [11C]UCB-J, which binds to SV2A, a marker of synaptic density. Levels of synaptic density were quantified by estimating binding potential (BPND) across four regions of interest: frontal cortex, striatum, hippocampus, and cerebellum.RESULTSPeople with AUD were on average(±SD) 43±13 years old and most met criteria for mild or moderate AUD. Controls were 37±12 years old. People with AUD had on average 11% lower [11C]UCB-J BPND than controls in the frontal cortex (F(1,62)=13.074, p<0.001), striatum (F(1,60)=10.283, p=0.002), hippocampus (F(1,60)=5.964, p=0.018), and trending in the same direction in cerebellum (F(1,50)=3.438, p=0.070). Among people with AUD, lower [11C]UCB-J BPND was significantly related to more drinks per drinking day in the frontal cortex (p=0.022) and striatum (p=0.026). People with AUD performed worse on executive function than controls (p=0.020), but this was not related to [11C]UCB-J BPND.CONCLUSIONSynaptic density deficits are evident, even in people with mild-to-moderate AUD, with greater deficits in those with greater drinking severity. These findings underscore the potential of synaptic restoration as a therapeutic target for AUD.TRIAL REGISTRATIONN/A.FUNDINGThis work was supported by the National Institute of Health.
{"title":"Higher drinking frequency corresponds to lower synaptic density in people with alcohol use disorder.","authors":"Yasmin Zakiniaeiz,Nakul R Raval,Will Riordan,Nabeel Nabulsi,Yiyun Huang,Brian Pittman,David Matuskey,Gustavo A Angarita,Robin Bonomi,Sherry A McKee,Ansel T Hillmer,Kelly P Cosgrove","doi":"10.1172/jci199989","DOIUrl":"https://doi.org/10.1172/jci199989","url":null,"abstract":"BACKGROUNDChronic alcohol use leads to synaptic dysfunction in preclinical studies. However, whether in vivo synaptic density deficits are found in people with alcohol use disorder (AUD) remains unclear.METHODSThirty-two people with AUD (17 women) and 29 controls (17 women) completed one positron emission tomography (PET) brain imaging scan with the radiotracer [11C]UCB-J, which binds to SV2A, a marker of synaptic density. Levels of synaptic density were quantified by estimating binding potential (BPND) across four regions of interest: frontal cortex, striatum, hippocampus, and cerebellum.RESULTSPeople with AUD were on average(±SD) 43±13 years old and most met criteria for mild or moderate AUD. Controls were 37±12 years old. People with AUD had on average 11% lower [11C]UCB-J BPND than controls in the frontal cortex (F(1,62)=13.074, p<0.001), striatum (F(1,60)=10.283, p=0.002), hippocampus (F(1,60)=5.964, p=0.018), and trending in the same direction in cerebellum (F(1,50)=3.438, p=0.070). Among people with AUD, lower [11C]UCB-J BPND was significantly related to more drinks per drinking day in the frontal cortex (p=0.022) and striatum (p=0.026). People with AUD performed worse on executive function than controls (p=0.020), but this was not related to [11C]UCB-J BPND.CONCLUSIONSynaptic density deficits are evident, even in people with mild-to-moderate AUD, with greater deficits in those with greater drinking severity. These findings underscore the potential of synaptic restoration as a therapeutic target for AUD.TRIAL REGISTRATIONN/A.FUNDINGThis work was supported by the National Institute of Health.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The lymphatic system maintains tissue fluid balance, and FOXC2 mutations cause lymphoedema-distichiasis syndrome, which is characterized by lymphatic valve defects. Although oscillatory shear stress regulates FOXC2 expression, other extracellular regulators remain unclear. In this study, we identified LPA4 and LPA6, two Gα12/Gα13-coupled receptors for the bioactive lipid lysophosphatidic acid (LPA), as key regulators of FOXC2 expression and lymphatic valve development. Lymphatic endothelial cell (LEC)-specific Lpa4;Lpa6-deficient mice exhibited impaired lymphatic valve formation and maintenance, which resembled phenotypes of LEC-specific Foxc2-deficient mice, including abnormal lymphatic vessel patterning. Mechanistically, lymphatic endothelial Lpa4/Lpa6 ablation reduced FOXC2 expression in vitro and in vivo. NF-κB was found essential for LPA-induced FOXC2 expression through the LPA4/LPA6-Gα12/Gα13-Rho kinase signaling axis. Accordingly, pharmacological inhibition of NF-κB and Rho kinase impaired lymphatic valve maintenance in mice. These results suggested that lymphatic endothelial LPA4 and LPA6 synergistically regulate FOXC2 expression through NF-κB activation and play an important role in lymphatic valve formation and maintenance. Our findings provide a molecular basis for lymphatic vessel development with a therapeutic potential for targeting lymphatic-associated diseases.
淋巴系统维持组织液平衡，FOXC2突变引起淋巴水肿-双支管综合征，其特征是淋巴瓣膜缺陷。虽然振荡剪切应力调节FOXC2表达，但其他细胞外调节因子尚不清楚。在本研究中，我们发现两个Gα12/ g α13偶联的生物活性脂质溶血磷脂酸（LPA）受体LPA4和LPA6是FOXC2表达和淋巴阀发育的关键调控因子。淋巴内皮细胞（LEC）特异性Lpa4；lpa6缺陷小鼠表现出淋巴瓣膜形成和维持受损，这与lec特异性foxc2缺陷小鼠的表型相似，包括异常的淋巴管模式。在机制上，淋巴内皮Lpa4/Lpa6消融降低了FOXC2的体外和体内表达。发现NF-κB通过LPA4/ lpa6 - g - α12/ g - α13- rho激酶信号轴对lpa诱导的FOXC2表达至关重要。因此，药理抑制NF-κB和Rho激酶可损害小鼠淋巴阀的维持。提示淋巴内皮细胞LPA4和LPA6通过NF-κB活化协同调节FOXC2表达，在淋巴阀形成和维持中发挥重要作用。我们的发现为淋巴管发育提供了分子基础，并具有靶向淋巴相关疾病的治疗潜力。
{"title":"Lysophosphatidic acid-mediated NF-κB activation promotes FOXC2 expression essential for lymphatic valve development.","authors":"Daisuke Yasuda,Nana Sato,Keisuke Yanagida,Tomomi Hashidate-Yoshida,Tomohiro Shiiya,Hideo Shindou,Atsuki Taira,Takashi Ebihara,Takao Shimizu,Masanori Hirashima,Seiya Mizuno,Satoru Takahashi,Satoshi Ishii","doi":"10.1172/jci193364","DOIUrl":"https://doi.org/10.1172/jci193364","url":null,"abstract":"The lymphatic system maintains tissue fluid balance, and FOXC2 mutations cause lymphoedema-distichiasis syndrome, which is characterized by lymphatic valve defects. Although oscillatory shear stress regulates FOXC2 expression, other extracellular regulators remain unclear. In this study, we identified LPA4 and LPA6, two Gα12/Gα13-coupled receptors for the bioactive lipid lysophosphatidic acid (LPA), as key regulators of FOXC2 expression and lymphatic valve development. Lymphatic endothelial cell (LEC)-specific Lpa4;Lpa6-deficient mice exhibited impaired lymphatic valve formation and maintenance, which resembled phenotypes of LEC-specific Foxc2-deficient mice, including abnormal lymphatic vessel patterning. Mechanistically, lymphatic endothelial Lpa4/Lpa6 ablation reduced FOXC2 expression in vitro and in vivo. NF-κB was found essential for LPA-induced FOXC2 expression through the LPA4/LPA6-Gα12/Gα13-Rho kinase signaling axis. Accordingly, pharmacological inhibition of NF-κB and Rho kinase impaired lymphatic valve maintenance in mice. These results suggested that lymphatic endothelial LPA4 and LPA6 synergistically regulate FOXC2 expression through NF-κB activation and play an important role in lymphatic valve formation and maintenance. Our findings provide a molecular basis for lymphatic vessel development with a therapeutic potential for targeting lymphatic-associated diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"259 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：