Pub Date : 2025-12-16DOI: 10.1097/hep.0000000000001621
Mario Matute-González, Maxime Ronot, Victoria Chernyak, Bruno Sangro, Jordi Rimola
In oncology, the radiological assessment of treatment response is crucial for predicting therapeutic efficacy in terms of survival, both in clinical trials and daily practice. However, this fundamental principle is often challenged in the context of HCC, where cirrhosis-related phenomena complicate radiological evaluation and impact patient prognosis beyond the oncological disease itself. In addition, the introduction of new therapeutic agents into the rapidly evolving landscape of systemic treatment further complicates this task, raising significant concerns about the validity of commonly used response criteria in this setting. Here, we aim to provide a critical view of tumor response evaluation to systemic therapy in HCC. First, we review the main treatment response criteria to systemic therapy, emphasizing the differences and limitations of RECIST 1.1 and mRECIST. Second, we delve into the challenges of radiological evaluation both in clinical trials and daily practice, with a particular focus on emerging approaches currently under investigation, such as immunotherapy-based downstaging and conversion therapy. Finally, we discuss emerging trends and future directions in radiological assessment techniques, including 3D imaging, artificial intelligence, and radiomics, and their potential impact on refining treatment evaluation in the era of precision oncology.
{"title":"Response evaluation to systemic therapy in HCC: Current challenges and future perspectives","authors":"Mario Matute-González, Maxime Ronot, Victoria Chernyak, Bruno Sangro, Jordi Rimola","doi":"10.1097/hep.0000000000001621","DOIUrl":"https://doi.org/10.1097/hep.0000000000001621","url":null,"abstract":"In oncology, the radiological assessment of treatment response is crucial for predicting therapeutic efficacy in terms of survival, both in clinical trials and daily practice. However, this fundamental principle is often challenged in the context of HCC, where cirrhosis-related phenomena complicate radiological evaluation and impact patient prognosis beyond the oncological disease itself. In addition, the introduction of new therapeutic agents into the rapidly evolving landscape of systemic treatment further complicates this task, raising significant concerns about the validity of commonly used response criteria in this setting. Here, we aim to provide a critical view of tumor response evaluation to systemic therapy in HCC. First, we review the main treatment response criteria to systemic therapy, emphasizing the differences and limitations of RECIST 1.1 and mRECIST. Second, we delve into the challenges of radiological evaluation both in clinical trials and daily practice, with a particular focus on emerging approaches currently under investigation, such as immunotherapy-based downstaging and conversion therapy. Finally, we discuss emerging trends and future directions in radiological assessment techniques, including 3D imaging, artificial intelligence, and radiomics, and their potential impact on refining treatment evaluation in the era of precision oncology.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"19 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759573","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 : 2025-12-16DOI: 10.1097/hep.0000000000001601
Sarah Khan
{"title":"PSC and HCC: Age and cirrhosis draw the line on risk.","authors":"Sarah Khan","doi":"10.1097/hep.0000000000001601","DOIUrl":"https://doi.org/10.1097/hep.0000000000001601","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"13 1","pages":"1"},"PeriodicalIF":13.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760032","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 : 2025-12-16DOI: 10.1097/hep.0000000000001603
Muhammed Dogukan Aksu
{"title":"Fraction the fat, find the disease: Proton density fat fraction (PDFF) in MASLD diagnosis.","authors":"Muhammed Dogukan Aksu","doi":"10.1097/hep.0000000000001603","DOIUrl":"https://doi.org/10.1097/hep.0000000000001603","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"20 1","pages":"6-7"},"PeriodicalIF":13.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760031","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 : 2025-12-16DOI: 10.1097/hep.0000000000001600
Robert M Wilechansky
{"title":"Breaching the blood-brain barrier: Functional MRI changes in covert hepatic encephalopathy.","authors":"Robert M Wilechansky","doi":"10.1097/hep.0000000000001600","DOIUrl":"https://doi.org/10.1097/hep.0000000000001600","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"93 1","pages":"4-5"},"PeriodicalIF":13.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760035","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 : 2025-12-16DOI: 10.1097/hep.0000000000001645
Xiao-Dong Zhou,Qin-Fen Chen,Qiong-Yue Fan,Seung Up Kim,Terry Cheuk-Fung Yip,Salvatore Petta,Atsushi Nakajima,Emmanuel Tsochatzis,Jérôme Boursier,Elisabetta Bugianesi,Hannes Hagström,Wah-Kheong Chan,Manuel Romero-Gomez,José Luis Calleja,Victor de Lédinghen,Laurent Castéra,Arun J Sanyal,George Boon-Bee Goh,Philip Noel Newsome,Jian-Gao Fan,Michelle Lai,Céline Fournier-Poizat,Hye Won Lee,Grace Lai-Hung Wong,Angelo Armandi,Ying Shang,Grazia Pennisi,Elba Llop,Masato Yoneda,Marc de Saint-Loup,Clemence M Canivet,Paloma Carrillo-Fernandez,Carmen Lara-Romero,Rocio Gallego-Durán,Amon Asgharpour,Kevin Kim-Jun Teh,Mandy Sau-Wai Chan,Huapeng Lin,Wen-Yue Liu,Giovanni Targher,Christopher D Byrne,Vincent Wai-Sun Wong,Ming-Hua Zheng,
BACKGROUNDCardio-kidney-metabolic (CKM) syndrome, a new framework integrating cardiovascular, renal, and metabolic dysfunction, remains inadequately characterized in metabolic dysfunction-associated steatotic liver disease (MASLD).OBJECTIVEWe investigated the relationships between CKM stages and liver fibrosis severity, progression, and the risk of liver-related events (LREs) in MASLD.DESIGNPatients with MASLD from the VCTE-Prognosis cohort were stratified according to CKM stages. Outcomes included the prevalence of advanced liver fibrosis (LSM ≥10 kPa), liver stiffness progression (≥20% increase and Baveno category upshift), and incident LREs. Associations were assessed using multivariable logistic regression and Cox proportional hazards models.RESULTSAmong 12,097 patients with MASLD, the prevalence of advanced liver fibrosis increased across CKM stages at baseline: 9.6% (CKM stage 0-1), 18.0% (CKM stage 2), and 31.6% (CKM stage 3-4). CKM stage 2 (adjusted-OR=1.663, 95%CI 1.444-1.915) and CKM stage 3-4 (adjusted-OR=2.575, 95%CI 2.109-3.144) were independently associated with advanced fibrosis. During a 4.5-year median follow-up, 716 patients (6.1%) experienced progression of liver stiffness and 352 patients (1.7%) developed LRE. Compared to CKM stage 0-1, the risk of liver stiffness progression was higher in CKM stage 2 (adjusted-HR=1.321, 95%CI 1.050-1.662; p=0.018) and CKM stage 3-4 (adjusted-HR=1.767, 95%CI 1.339-2.330; p<0.001). In contrast, only CKM stage 3-4 was significantly associated with an increased risk of LREs (adjusted-HR=1.975, 95%CI 1.245-3.133; p=0.004).CONCLUSIONCKM stages are independently associated with the severity and progression of liver fibrosis in MASLD. CKM stage 2 significantly increases liver stiffness progression without excess LRE risk, while CKM stage 3-4 confers the highest risk for liver-related outcomes.
{"title":"Cardiovascular-Kidney-Metabolic syndrome and the risk of liver fibrosis progression and liver-related events in MASLD.","authors":"Xiao-Dong Zhou,Qin-Fen Chen,Qiong-Yue Fan,Seung Up Kim,Terry Cheuk-Fung Yip,Salvatore Petta,Atsushi Nakajima,Emmanuel Tsochatzis,Jérôme Boursier,Elisabetta Bugianesi,Hannes Hagström,Wah-Kheong Chan,Manuel Romero-Gomez,José Luis Calleja,Victor de Lédinghen,Laurent Castéra,Arun J Sanyal,George Boon-Bee Goh,Philip Noel Newsome,Jian-Gao Fan,Michelle Lai,Céline Fournier-Poizat,Hye Won Lee,Grace Lai-Hung Wong,Angelo Armandi,Ying Shang,Grazia Pennisi,Elba Llop,Masato Yoneda,Marc de Saint-Loup,Clemence M Canivet,Paloma Carrillo-Fernandez,Carmen Lara-Romero,Rocio Gallego-Durán,Amon Asgharpour,Kevin Kim-Jun Teh,Mandy Sau-Wai Chan,Huapeng Lin,Wen-Yue Liu,Giovanni Targher,Christopher D Byrne,Vincent Wai-Sun Wong,Ming-Hua Zheng, ","doi":"10.1097/hep.0000000000001645","DOIUrl":"https://doi.org/10.1097/hep.0000000000001645","url":null,"abstract":"BACKGROUNDCardio-kidney-metabolic (CKM) syndrome, a new framework integrating cardiovascular, renal, and metabolic dysfunction, remains inadequately characterized in metabolic dysfunction-associated steatotic liver disease (MASLD).OBJECTIVEWe investigated the relationships between CKM stages and liver fibrosis severity, progression, and the risk of liver-related events (LREs) in MASLD.DESIGNPatients with MASLD from the VCTE-Prognosis cohort were stratified according to CKM stages. Outcomes included the prevalence of advanced liver fibrosis (LSM ≥10 kPa), liver stiffness progression (≥20% increase and Baveno category upshift), and incident LREs. Associations were assessed using multivariable logistic regression and Cox proportional hazards models.RESULTSAmong 12,097 patients with MASLD, the prevalence of advanced liver fibrosis increased across CKM stages at baseline: 9.6% (CKM stage 0-1), 18.0% (CKM stage 2), and 31.6% (CKM stage 3-4). CKM stage 2 (adjusted-OR=1.663, 95%CI 1.444-1.915) and CKM stage 3-4 (adjusted-OR=2.575, 95%CI 2.109-3.144) were independently associated with advanced fibrosis. During a 4.5-year median follow-up, 716 patients (6.1%) experienced progression of liver stiffness and 352 patients (1.7%) developed LRE. Compared to CKM stage 0-1, the risk of liver stiffness progression was higher in CKM stage 2 (adjusted-HR=1.321, 95%CI 1.050-1.662; p=0.018) and CKM stage 3-4 (adjusted-HR=1.767, 95%CI 1.339-2.330; p<0.001). In contrast, only CKM stage 3-4 was significantly associated with an increased risk of LREs (adjusted-HR=1.975, 95%CI 1.245-3.133; p=0.004).CONCLUSIONCKM stages are independently associated with the severity and progression of liver fibrosis in MASLD. CKM stage 2 significantly increases liver stiffness progression without excess LRE risk, while CKM stage 3-4 confers the highest risk for liver-related outcomes.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"13 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760037","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 : 2025-12-16DOI: 10.1097/hep.0000000000001602
Michael Eiswerth,Juan Pablo Arab
{"title":"The roadMAP of how terlipressin reverses HRS-AKI.","authors":"Michael Eiswerth,Juan Pablo Arab","doi":"10.1097/hep.0000000000001602","DOIUrl":"https://doi.org/10.1097/hep.0000000000001602","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"14 1","pages":"2-3"},"PeriodicalIF":13.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760034","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 : 2025-12-15DOI: 10.1097/hep.0000000000001630
Marta Fortuny, Antonio De Rosa, Ignacio Roca, Dan Ouchi, Elisaul Suárez, Andrea Cadiz, Mario Matute-González, Andrew M. Moon, Jordi Rimola, Ferran Torres, Maria Reig
Background & Aims: Macrovascular invasion (MaVI) defines advanced-stage HCC and typically mandates systemic therapy, yet some guidelines advocate surgery or locoregional approaches. We conducted a systematic review and meta-analysis of overall survival (OS) in HCC with MaVI treated with approaches other than systemic therapy, enforcing stringent inclusion criteria to exclude studies lacking a minimal prognostic dataset and to improve cohort comparability. Approach & Results: PRISMA-guided methods were used (CRD420251051847). PubMed was searched (January-2008 to November-2024). Eligible studies reported OS for HCC with MaVI and provided baseline performance status and liver function; studies without adequate prognostic information were excluded. Data on OS at 1, 2, 3, and 5-year were extracted, and heterogeneity was assessed. Seventy-three studies met criteria [104 treatment arms;10,329 patients]. Despite rigorous identification process, substantial heterogeneity persisted for most modalities (I²>80%), precluding robust pooling. Transarterial-radioembolization (TARE) monotherapy was the only treatment with low heterogeneity (I²=0%) and showed a pooled 1-year OS of 34% (95%CI:2–48%). Apparent advantages of sequential strategies likely reflected confounding by indication and immortal-time bias, as only patients who lived long enough and were sufficiently fit proceeded through the full sequence. Data completeness declined beyond 12 months (missing OS: 0% at 1-year; 17.3% at 2-year; 32.7% at 3-year; 70.2% at 5-year). Conclusions: In HCC with MaVI, 1-year OS is the most comparable endpoint across modalities. This analysis identifies TARE as the only consistently reproducible option, showing a 1-year survival of 34%. In contrast, surgery and sequential therapies remain confounded by substantial heterogeneity. Accordingly, stratified head-to-head trials comparing alternative modalities against immunotherapy are warranted.
{"title":"Hepatocellular carcinoma with macrovascular invasion: Review and survival meta-analysis of initial local therapy using minimal prognostic criteria","authors":"Marta Fortuny, Antonio De Rosa, Ignacio Roca, Dan Ouchi, Elisaul Suárez, Andrea Cadiz, Mario Matute-González, Andrew M. Moon, Jordi Rimola, Ferran Torres, Maria Reig","doi":"10.1097/hep.0000000000001630","DOIUrl":"https://doi.org/10.1097/hep.0000000000001630","url":null,"abstract":"Background & Aims: Macrovascular invasion (MaVI) defines advanced-stage HCC and typically mandates systemic therapy, yet some guidelines advocate surgery or locoregional approaches. We conducted a systematic review and meta-analysis of overall survival (OS) in HCC with MaVI treated with approaches other than systemic therapy, enforcing stringent inclusion criteria to exclude studies lacking a minimal prognostic dataset and to improve cohort comparability. Approach & Results: PRISMA-guided methods were used (CRD420251051847). PubMed was searched (January-2008 to November-2024). Eligible studies reported OS for HCC with MaVI and provided baseline performance status and liver function; studies without adequate prognostic information were excluded. Data on OS at 1, 2, 3, and 5-year were extracted, and heterogeneity was assessed. Seventy-three studies met criteria [104 treatment arms;10,329 patients]. Despite rigorous identification process, substantial heterogeneity persisted for most modalities (I²>80%), precluding robust pooling. Transarterial-radioembolization (TARE) monotherapy was the only treatment with low heterogeneity (I²=0%) and showed a pooled 1-year OS of 34% (95%CI:2–48%). Apparent advantages of sequential strategies likely reflected confounding by indication and immortal-time bias, as only patients who lived long enough and were sufficiently fit proceeded through the full sequence. Data completeness declined beyond 12 months (missing OS: 0% at 1-year; 17.3% at 2-year; 32.7% at 3-year; 70.2% at 5-year). Conclusions: In HCC with MaVI, 1-year OS is the most comparable endpoint across modalities. This analysis identifies TARE as the only consistently reproducible option, showing a 1-year survival of 34%. In contrast, surgery and sequential therapies remain confounded by substantial heterogeneity. Accordingly, stratified head-to-head trials comparing alternative modalities against immunotherapy are warranted.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"7 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759710","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 : 2025-12-15DOI: 10.1097/hep.0000000000001639
Qi Ruan, Tao Chen, Minwoo Kim, Haotian Yang, Debottam Sinha, Yaowu He, Lez Burke, Lashith Wickramasuriya, Lu Cao, Weikang Yan, John Hooper, Haolu Wang, Kim Bridle, Janin Chandra, Darrell Crawford, Xiaowen Liang
Background and Aims: The poor response to current systemic treatments in liver cancer has been associated with the activation of cancer-associated fibroblasts (CAFs). Herein, we aimed to investigate the effects of chemotherapy on hepatic stellate cells (HSCs), the main origin of CAFs in liver cancer, and regulate HSC activation to improve treatment efficacy. Approach and Results: CAF subpopulations and alpha-smooth muscle actin (αSMA) expression were analysed using a single-cell RNA sequencing dataset and immunohistochemical staining in patients. αSMA expression was significantly increased as the proportion of CAFs enriched by COL1A1+ and ACTA2+ subpopulations in patients after transarterial chemoembolisation. In vitro experiments demonstrated that cisplatin activated HSCs through a paracrine effect of excessive reactive oxygen species (ROS) generated from tumour cells of hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) origin. RNA sequencing revealed that the PI3K signalling pathway underlined the activation of HSCs in response to excessive ROS. This was further analysed in HCC mouse models on non-fibrotic and fibrotic livers. 12-parameter flow cytometry panel validated a significant increase in activated CAF subsets in tumours following cisplatin treatment. Alpelisib, an α-specific PI3K inhibitor, selectively targeted PI3K p110α and completely inhibited HSC activation induced by cisplatin. A marked decrease in fibrosis areas was achieved along with a significant reduction of tumour burden in murine HCC models. Conclusion: This study demonstrates a role of platinum-based chemotherapy on HSC activation in liver cancer. Selective targeting of PI3K p110α may provide a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response.
{"title":"An α-specific PI3K inhibitor improves chemotherapy efficacy by inhibiting hepatic stellate cell activation in liver cancer","authors":"Qi Ruan, Tao Chen, Minwoo Kim, Haotian Yang, Debottam Sinha, Yaowu He, Lez Burke, Lashith Wickramasuriya, Lu Cao, Weikang Yan, John Hooper, Haolu Wang, Kim Bridle, Janin Chandra, Darrell Crawford, Xiaowen Liang","doi":"10.1097/hep.0000000000001639","DOIUrl":"https://doi.org/10.1097/hep.0000000000001639","url":null,"abstract":"Background and Aims: The poor response to current systemic treatments in liver cancer has been associated with the activation of cancer-associated fibroblasts (CAFs). Herein, we aimed to investigate the effects of chemotherapy on hepatic stellate cells (HSCs), the main origin of CAFs in liver cancer, and regulate HSC activation to improve treatment efficacy. Approach and Results: CAF subpopulations and alpha-smooth muscle actin (αSMA) expression were analysed using a single-cell RNA sequencing dataset and immunohistochemical staining in patients. αSMA expression was significantly increased as the proportion of CAFs enriched by COL1A1+ and ACTA2+ subpopulations in patients after transarterial chemoembolisation. <jats:italic toggle=\"yes\">In vitro</jats:italic> experiments demonstrated that cisplatin activated HSCs through a paracrine effect of excessive reactive oxygen species (ROS) generated from tumour cells of hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) origin. RNA sequencing revealed that the PI3K signalling pathway underlined the activation of HSCs in response to excessive ROS. This was further analysed in HCC mouse models on non-fibrotic and fibrotic livers. 12-parameter flow cytometry panel validated a significant increase in activated CAF subsets in tumours following cisplatin treatment. Alpelisib, an α-specific PI3K inhibitor, selectively targeted PI3K p110α and completely inhibited HSC activation induced by cisplatin. A marked decrease in fibrosis areas was achieved along with a significant reduction of tumour burden in murine HCC models. Conclusion: This study demonstrates a role of platinum-based chemotherapy on HSC activation in liver cancer. Selective targeting of PI3K p110α may provide a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"20 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759681","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}
BACKGROUND AND AIMSLiver cirrhosis, a leading global cause of mortality, is marked by progressive fibrosis and immune dysregulation. Tissue-resident memory T (TRM) cells, particularly γδ T cells, are emerging as critical regulators of hepatic immunity; however, their role in fibrogenesis remains poorly understood.APPROACH AND RESULTSThrough single-cell RNA sequencing and flow cytometry, we show that CD69⁺CXCR6⁺ γδ T cells are enriched in healthy livers and produce IFN-γ and IL-2 but significantly depleted in cirrhotic tissue, correlating with disease severity. In a murine fibrosis model, CXCR6⁺ γδ T cells limited fibrosis progression by inducing hepatic stellate cell apoptosis via FasL-Fas signaling. Adoptive transfer of CXCR6⁺ γδ T cells significantly mitigated fibrosis, whereas CXCR6- γδ T cells showed no such effect.CONCLUSIONLiver-resident CD69⁺CXCR6⁺ γδ T cells constitute a protective immune subset that limit fibrosis development and progression. Enhancing the function or abundance of this population may offer a promising immunotherapeutic strategy for liver cirrhosis.
{"title":"CXCR6 defines a distinct resident state in γδ T cells for protecting from liver cirrhosis.","authors":"Jiahao Ji,Zhitao Chen,Wenjing He,Yanxu Chen,Dongmei Ye,Yingqian Zhong,Xiaomin Shi,Xiaojun Ouyang,Zhimin Zeng,Qianyu Ye,Xiaoshun He,Zhinan Yin,Jianlei Hao,Yifang Gao","doi":"10.1097/hep.0000000000001643","DOIUrl":"https://doi.org/10.1097/hep.0000000000001643","url":null,"abstract":"BACKGROUND AND AIMSLiver cirrhosis, a leading global cause of mortality, is marked by progressive fibrosis and immune dysregulation. Tissue-resident memory T (TRM) cells, particularly γδ T cells, are emerging as critical regulators of hepatic immunity; however, their role in fibrogenesis remains poorly understood.APPROACH AND RESULTSThrough single-cell RNA sequencing and flow cytometry, we show that CD69⁺CXCR6⁺ γδ T cells are enriched in healthy livers and produce IFN-γ and IL-2 but significantly depleted in cirrhotic tissue, correlating with disease severity. In a murine fibrosis model, CXCR6⁺ γδ T cells limited fibrosis progression by inducing hepatic stellate cell apoptosis via FasL-Fas signaling. Adoptive transfer of CXCR6⁺ γδ T cells significantly mitigated fibrosis, whereas CXCR6- γδ T cells showed no such effect.CONCLUSIONLiver-resident CD69⁺CXCR6⁺ γδ T cells constitute a protective immune subset that limit fibrosis development and progression. Enhancing the function or abundance of this population may offer a promising immunotherapeutic strategy for liver cirrhosis.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"38 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728560","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}
Background and Aims: Intrahepatic cholangiocarcinoma (iCCA) is a highly metastatic tumor type, and iCCA with intrahepatic metastasis is associated with poor prognosis. Previous studies have confirmed that the tumor microenvironment (TME) is closely related to tumor metastasis. However, the state of the TME during iCCA liver metastasis remains unknown. Approach and Results: We profiled 28 specimens from 16 patients with iCCA (with and without intrahepatic metastasis) using integrated single-cell and spatial transcriptomics, bulk RNA sequencing, whole-exome sequencing, and in vivo and in vitro functional experiments to characterize the specific TME changes during iCCA liver metastasis. we identified the metastatic tumor cells, COL3A1 + epithelial cells, and revealed that COL3A1 + epithelial cells-endothelial-to-mesenchymal transition cells crosstalk promoted tumor invasion by inducing mesenchymal transformation of endothelial cells, while COL3A1 + epithelial cells-VEGFA + CCL4 + neutrophils crosstalk promoted tumor colonization by forming neutrophil extracellular traps. Conclusions: We revealed the key biological mechanisms involved in the invasion and colonization phases of iCCA liver metastasis. Moreover, we provide valuable data for understanding iCCA liver metastasis and a possible avenue for the treatment of advanced iCCA.
{"title":"Spatiotemporal landscape of intrahepatic cholangiocarcinoma liver metastasis at the single-cell level","authors":"Ziyu Xun, Hao Wang, Zhengfeng Xuan, Kexu Xiong, Nan Zhang, Junyu Long, Huishan Sun, Yiran Li, Chengpei Zhu, Mingjian Piao, Ting Zhang, Longhao Zhang, Shuofeng Li, Chengjie Li, Jiongyuan Li, Boyu Sun, Zixiang Zhou, Shanshan Wang, Ziyue Huang, Kai Liu, Yang Tan, Xiaohua Shi, Xiaobo Yang, Hanping Wang, Ling Lu, Haitao Zhao","doi":"10.1097/hep.0000000000001641","DOIUrl":"https://doi.org/10.1097/hep.0000000000001641","url":null,"abstract":"Background and Aims: Intrahepatic cholangiocarcinoma (iCCA) is a highly metastatic tumor type, and iCCA with intrahepatic metastasis is associated with poor prognosis. Previous studies have confirmed that the tumor microenvironment (TME) is closely related to tumor metastasis. However, the state of the TME during iCCA liver metastasis remains unknown. Approach and Results: We profiled 28 specimens from 16 patients with iCCA (with and without intrahepatic metastasis) using integrated single-cell and spatial transcriptomics, bulk RNA sequencing, whole-exome sequencing, and in vivo and in vitro functional experiments to characterize the specific TME changes during iCCA liver metastasis. we identified the metastatic tumor cells, COL3A1 <jats:sup>+</jats:sup> epithelial cells, and revealed that COL3A1 <jats:sup>+</jats:sup> epithelial cells-endothelial-to-mesenchymal transition cells crosstalk promoted tumor invasion by inducing mesenchymal transformation of endothelial cells, while COL3A1 <jats:sup>+</jats:sup> epithelial cells-VEGFA <jats:sup>+</jats:sup> CCL4 <jats:sup>+</jats:sup> neutrophils crosstalk promoted tumor colonization by forming neutrophil extracellular traps. Conclusions: We revealed the key biological mechanisms involved in the invasion and colonization phases of iCCA liver metastasis. Moreover, we provide valuable data for understanding iCCA liver metastasis and a possible avenue for the treatment of advanced iCCA.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"1 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717479","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}
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