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Hippo(YAP)-autophagy axis protects against hepatic ischemia-reperfusion injury through JNK signaling

Chinese Medical Journal 2024年第6期137卷 657-668页

作者： Shuguang Zhu Xiaowen Wang Haoqi Chen Wenfeng Zhu Xuejiao Li Ruiwen Cui Xiaomeng Yi Xiaolong Chen Hua Li Genshu Wang department of hepatic surgery Liver TransplantationThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China department of Hepatology lab The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China department of General surgery The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China department of Organ transplantation The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China department of Renal transplantation Guangdong Provincial Hospital of Chinese MedicineGuangzhouGuangdong 510630China department of Surgical Intensive Care Unit The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China department of hepatic surgery Liver TransplantationGuangdong Provincial Hospital of Chinese MedicineGuangzhouGuangdong 510630China

Background:hepatic ischemia-reperfusion injury(HIRI)remains a common complication during liver transplantation(LT)in patients.As a key downstream effector of the Hippo pathway,Yes-associated protein(YAP)has been reported to be involved in various physiological and pathological processes.However,it remains elusive whether and how YAP may control autophagy activation during ischemia-reperfusion.Methods:Human liver tissues from patients who had undergone LT were obtained to evaluate the correlation between YAP and autophagy activation.Both an in vitro hepatocyte cell line and in vivo liver-specific YAP knockdown mice were used to establish the hepatic ischemia-reperfusion models to determine the role of YAP in the activation of autophagy and the mechanism of regulation.Results:Autophagy was activated in the post-perfusion liver grafts during LT in patients,and the expression of YAP positively correlated with the autophagic level of hepatocytes.liver-specific knockdown of YAP inhibited hepatocytes autophagy upon hypoxia-reoxygenation and HIRI(P<0.05).YAP deficiency aggravated HIRI by promoting the apoptosis of hepatocytes both in the in vitro and in vivo models(P<0.05).Attenuated HIRI by overexpression of YAP was diminished after the inhibition of autophagy with 3-methyladenine.In addition,inhibiting autophagy activation by YAP knockdown exacerbated mitochondrial damage through increasing reactive oxygen species(P<0.05).Moreover,the regulation of autophagy by YAP during HIRI was mediated by AP1(c-Jun)N-terminal kinase(JNK)signaling through binding to the transcriptional enhanced associate domain(TEAD).Conclusions:YAP protects against HIRI by inducing autophagy via JNK signaling that suppresses the apoptosis of hepatocytes.Targeting Hippo(YAP)-JNK-autophagy axis may provide a novel strategy for the prevention and treatment of HIRI.

关键词： YAP-signaling proteins Autophagy c-Jun N-terminal kinase Ischemia-reperfusion injury liver transplantation

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Ex vivo liver resection and auto-transplantation as an alternative for the treatment of liver malignancies: Progress and challenges

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Hepatobiliary & Pancreatic Diseases International 2024年第2期23卷 117-122页

作者： Xin Yang Lu Lu Wen-Wei Zhu Yi-Feng Tao Cong-Huan Shen Jin-Hong Chen Zheng-Xin Wang Lun-Xiu Qin Hepatobiliary surgery and liver transplantation centers Department of General SurgeryHuashan Hospital&Cancer Metastasis InstituteFudan UniversityShanghai 200040China

Hepatectomy is still the major curative treatment for patients with liver malignancies.However,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the retrohepatic inferior vena cava and hepatic veins.Ex vivo liver resection and auto-transplantation(ELRA),a hybrid technique of the traditional liver resection and transplantation,has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation.Due to its technical difficulty,ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation.The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases,especially in the advanced alveolar echinococcosis.Recently,the application of ELRA for liver malignances has gained more attention.However,standardization of clinical practice norms and international consensus are still lacking.The prognostic impact in these oncologic patients also needs further evaluation.In this review,we summarized the principles and recent progresses on ELRA.

关键词： Ex vivo liver resection liver auto-transplantation Oncology liver malignancies

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Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma:a multicenter cohort study in China

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Cancer Biology & Medicine 2024年第4期21卷 347-362页

作者： Jian Chen Zhe Yang Fengqiang Gao Zhisheng Zhou Junli Chen Di Lu Kai Wang Meihua Sui Zhengxin Wang Wenzhi Guo Guoyue Lyu Haizhi Qi Jinzhen Cai Jiayin Yang Shusen Zheng Xiao Xu Zhejiang University School of Medicine Hangzhou 310030China Institute of Organ transplantation Zhejiang UniversityHangzhou 310030China department of Hepatobiliary and Pancreatic surgery Shulan Hospital of HangzhouHangzhou 310006China National center for Healthcare Quality Management in liver Transplant Hangzhou 310003China department of General surgery Huashan HospitalFudan UniversityShanghai 200040China department of Hepatobiliary and Pancreatic surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China department of Hepatobiliary and Pancreatic surgery The First Hospital of Jilin UniversityChangchun 130021China department of liver transplantation Second Xiangya HospitalCentral South UniversityChangsha 410008China department of Organ transplantation center The Affiliated Hospital of Qingdao UniversityQingdao 266003China department of liver surgery and liver transplantation center West China HospitalSichuan UniversityChengdu 610044China NHC Key Laboratory of Combined Multi-organ transplantation Hangzhou 310003China department of Hepatobiliary and Pancreatic surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Objective:Sex-specific differences are observed in various liver diseases,but the influence of sex on the outcomes of hepatocellular carcinoma(HCC)after liver transplantation(LT)remains to be determined.This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC.Methods:Data for recipients with HCC registered in the China liver Transplant Registry between January 2015 and December 2020 were analyzed.The associations between donor,recipient,or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching(PSM).The survival associated with different sex-based donor-recipient transplant patterns was further studied.Results:Among 3,769 patients enrolled in this study,the 1-,3-,and 5-year overall survival(OS)rates of patients with HCC after LT were 96.1%,86.4%,and 78.5%,respectively,in female recipients,and 95.8%,79.0%,and 70.7%,respectively,in male recipients after PSM(P=0.009).However,the OS was comparable between recipients with female donors and male donors.Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival(HR=1.381,P=0.046).Among the donor-recipient transplant patterns,the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival(Plivers from male donors may provide the most benefit to female recipients.Our results indicate that sex should be considered as a critical factor in organ allocation.

关键词： Sex liver transplantation hepatocellular carcinoma outcome recipient donor

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Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma:A comprehensive review

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World Journal of Hepatology 2024年第4期16卷 537-549页

作者： Jing-Jing Li Jia-Xi Mao Han-Xiang Zhong Yuan-Yu Zhao Fei Teng Xin-Yi Lu Li-Ye Zhu Yang Gao Hong Fu Wen-Yuan Guo department of liver surgery and Organ transplantation Shanghai Changzheng HospitalNaval Medical UniversityShanghai 200003China

The tumor microenvironment is a complex network of cells,extracellular matrix,and signaling molecules that plays a critical role in tumor progression and metastasis.Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits.However,recent studies have shown that lymphatic endothelial cells(LECs)and blood endothelial cells(BECs)also play multifaceted roles in the tumor microenvironment beyond their structural functions,particularly in hepatocellular carcinoma(HCC).This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC,including their involvement in angiogenesis,immune modulation,lymphangiogenesis,and metastasis.By providing a detailed account of the complex interplay between LECs,BECs,and tumor cells,this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.

关键词： Lymphatic endothelial cells Blood endothelial cells Hepatocellular carcinoma Tumor microenvironment

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Comprehensive review of hepatocellular carcinoma with portal vein tumor thrombus:State of art and future perspectives

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 221-227页

作者： Paschalis Gavriilidis Timothy M Pawlik Daniel Azoulay department of surgery Colchester General HospitalTurner RoadColchester CO45JLUK department of surgery The Ohio State Wexner Medical CenterJames Comprehensive Cancer CenterColumbusOHUSA department of Hepato-Biliary and liver transplantation surgery Paul Brousse University HospitalParis-Saclay UniversityVillejuif 94800France

Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated.Data sources:A systematic search of MEDLINE(PubMed),Embase,Cochrane Library and Database for Systematic Reviews(CDSR),Google Scholar,and National Institute for Health and Clinical Excellence(NICE)databases until December 2022 was conducted using free text and MeSH terms:hepatocellular carcinoma,portal vein tumor thrombus,portal vein thrombosis,vascular invasion,liver and/or hepatic resection,liver transplantation,and systematic review.Results:centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy.Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus,accurate identification of the subgroups of patients who may benefit from resection,as well as meticulous surgical technique.This review addressed five specific areas:(a)formation of PVTT;(b)classifications of PVTT;(c)controversies related to clinical guidelines;(d)surgical treatments versus non-surgical approaches;and(e)characterization of surgical techniques correlated with classifications of PVTT.Conclusions:Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.

关键词： Hepatectomy liver surgery liver neoplasms Portal vein tumor thrombus

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Current status of liver transplantation for human immunodeficiency virus-infected patients in China's Mainland

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World Journal of Gastroenterology 2024年第14期30卷 1958-1962页

作者： Jian-Xin Tang Dong Zhao department of liver surgery and Organ transplantation center Shenzhen Third People’s HospitalThe Second Affiliated Hospital of Southern University of Science and TechnologyNational Clinical Research Center for Infectious DiseaseShenzhen 518000Guangdong ProvinceChina

According to the report from the Chinese center for Disease Control and Prevention,the prevalence of human immunodeficiency virus(HIV)infection exceeded 1.2 million individuals by the year 2022,with an annual increase of about 80000 cases.The overall prevalence of hepatitis B surface antigen among individuals co-infected with HIV reached 13.7%,almost twice the rate of the general population in China.In addition to the well-documented susceptibility to opportunistic infections and new malignancies,HIV infected patients frequently experience liver-related organ damage,with the liver and kidneys being the most commonly affected.This often leads to the development of end-stage liver and kidney diseases.Therefore,organ transplantation has emerged as an important part of active treatment for HIV infected patients.However,the curative effect is not satisfactory.HIV infection has been considered a contraindication for organ transplantation.Until the emergence of highly active anti-retroviral therapy in 1996,the once intractable replication of retrovirus was effectively inhibited.With prolonged survival,the failure of important organs has become the main cause of death among HIV patients.Therefore,transplant centers worldwide have resu-med exploration of organ transplantation for HIV-infected individuals and reached a positive conclusion.This study provides an overview of the current landscape of HIV-positive patients receiving liver transplantation(LT)in main-land China.To date,our transplant center has conducted LT for eight end-stage liver disease patients co-infected with HIV,and all but one,who died two months postoperatively due to sepsis and progressive multi-organ failure,have survived.Comparative analysis with hepatitis B virus-infected patients during the same period revealed no statistically significant differences in acute rejection reactions,cytomegalovirus infection,bacteremia,pulmonary infections,acute kidney injury,new-onset cancers,or vascular and biliary complications.

关键词： liver transplantation Human immunodeficiency virus Infection Hepatitis B virus End-stage liver disease China'Mainland

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Incidence,Risk Factors,and Prognosis of Patients with Hepatocellular Carcinoma and Brain Metastases

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Current Medical Science 2024年第1期44卷 180-186页

作者： Jin-cheng FENG Ying HE Georgios Polychronidis Jian XIN Shen YOU Jun XIONG department of liver transplantation Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Key Laboratory of Transplant Engineering and Immunology Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China department of General Visceral and Transplant SurgeryUniversity of HeidelbergIm Neuenheimer Feld 110Heidelberg 69120Germany department of Hepatobiliary and Pancreatic surgery Fujian Provincial HospitalFuzhou 350001China

Objective Brain metastases significantly impact the clinical course of patients with hepatocellular carcinoma(HCC).This study aimed to examine the age-related incidence,demographics,and survival of patients with HCC and brain metastases.Methods Data of HCC patients from 2010 to 2015 in the Surveillance,Epidemiology,and End Results(SEER)Registry were screened for the presence of brain metastases.They were stratified by age and ethnicity.Multivariable logistic and Cox regression analyses were used to identify factors associated with brain metastases and those with overall survival(OS)and liver cancer-specific survival(CSS),respectively.Results A total of 141 HCC patients presenting with brain metastases were identified,accounting for 0.35% of all HCC patients and 2.37% of patients with metastatic disease.Among all HCC patients,the incidence rate was the highest among patients aged 30-49 years old(0.47%).Ethnicity was not associated with the presence of brain metastases at the time of HCC diagnosis.However,African-American patients presented with a significantly lower disease-specific survival[median time:1 month;interquartile range(IQR):0-3.0 months].Initial lung or bone metastasis was independently associated with an increased risk of the presence of brain metastases[odds ratio(OR):12.62,95% confidence interval(CI):8.40-18.97]but was not associated with a worse OS or CSS among those with brain metastases.Conclusion This study identified the age-related incidence and risk factors of brain metastases in HCC patients.These results may contribute to the consideration of brain screening among patients with initial metastatic HCC with lung or bone metastases,and influence the counseling of this patient population regarding their prognosis.

关键词： brain metastases hepatocellular carcinoma age-related incidence cancer-specific survival overall survival

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Gallbladder carcinosarcoma with a poor prognosis: A case report

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World Journal of Clinical Cases 2024年第10期12卷 1817-1823页

作者： Yi Dai Min Meng Qi-Zhi Luo Yuan-Jun Liu Fan Xiao Chun-Hua Wang department of Hepatobiliary surgery Suining Central HospitalSuining 629000Sichuan ProvinceChina The Cancer center Suining Central HospitalSuining 629000Sichuan ProvinceChina department of Pathology Suining Central HospitalSuining 629000Sichuan ProvinceChina department of liver surgery&liver transplantation West China Hospital of Sichuan UniversityChengdu 610041Sichuan ProvinceChina

BACKGROUND Carcinosarcoma of the gallbladder is a rare malignant tumor with a very poor prognosis.To date,only approximately 100 patients have been reported in the English literature.The prognosis of this tumor type is poor,the preoperative diagnosis is difficult,and there is a possibility of a misdiagnosis.We present an unsuccessful case of carcinosarcoma of the gallbladder with a preoperative misdiagnosis and rapid early postoperative recurrence.Therefore,we have a deeper understanding of the poor prognosis of gallbladder carcinosarcoma(GBC)patients.CASE SUMMARY The patient is a 65-year-old male.He was admitted to the hospital because of right upper abdomen distending pain and discomfort for half a month.Abdominal magnetic resonance imaging revealed a polycystic mass in the right lobe of the liver and the fossa of the gallbladder.After admission,the patient was diagnosed with a liver abscess,which was treated by abscess puncture drainage.Obviously,this treatment was unsuccessful.Hepatectomy and cholecystectomy were performed one month after the puncture.Postoperative pathologic examination revealed carcinosarcoma of the gallbladder,and the resected specimen contained two tumor components.One month after surgery,the patient's tumor recurred in situ and started to compress the duodenum,resulting in duodenal obstruction and bleeding.The treatment was not effective.The patient died of gastrointestinal hemorrhage and hypovolemic shock.CONCLUSION Carcinosarcoma of the gallbladder is a rare malignant tumor that is easily misdiagnosed preoperatively and has a poor prognosis.

关键词： Gallbladder disease Carcinosarcoma Misdiagnosis Poor prognosis Pathological diagnosis Recurrence Case report

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Metformin and pancreatic neuroendocrine tumors:A systematic review and meta-analysis

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World Journal of Gastroenterology 2024年第7期30卷 759-769页

作者： Maja Cigrovski Berkovic Alessandro Coppola Vibor Sesa Anna Mrzljak Quirino Lai department for Sport and Exercise Medicine Faculty of Kinesiology University of ZagrebZagreb 10000Croatia department of surgery Sapienza University of RomeRome 00185Italy department of Gastroenterology and Hepatology Liver Transplant CenterUniversity Hospital Centre ZagrebZagreb 10000Croatia department of Medicine School of MedicineZagreb 10000Croatia General surgery and Organ transplantation Unit Department of SurgerySapienza University of RomeRome 00018Italy

BACKGROUND Most patients with advanced pancreatic neuroendocrine tumors(pNETs)die due to tumor progression.Therefore,identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant.In this perspective,metformin is emerging as a molecule of interest.Retrospective studies have described metformin,a widely used agent for the treatment of patients with type 2 diabetes mellitus(T2DM),to be effective in modulating different tumor-related events,including cancer incidence,recurrence and survival by inhibiting mTOR phosphorylation.This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.AIM To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and posttreatment outcomes of pNET.METHODS A systematic review of the published literature was undertaken,focusing on the role of T2DM and metformin in insurgence and prognosis of pNET,measured through outcomes of tumor-free survival(TFS),overall survival and progression free survival.RESULTS A total of 13 studies(5674 patients)were included in this review.Analysis of 809 pNET cases from five retrospective studies(low study heterogeneity with I^(2)=0%)confirms the correlation between T2DM and insurgence of pNET(OR=2.13,95%CI=1.56-4.55;P<0.001).The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients(hazard ratio=1.84,95%CI=0.78-2.90;P<0.001).The study heterogeneity was intermediate,with I^(2)=51%.A few studies limited the possibility of performing pooled analysis in the setting of metformin;therefore,results were heterogeneous,with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.CONCLUSION T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients.Unfortunately,a few studies wi

关键词： Pancreatic neuroendocrine tumors Type 2 diabetes mellitus Prognosis Treatment Metformin

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Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

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Cancer Communications 2024年第2期44卷 226-250页

作者： Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi department of liver surgery and transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationShanghaiP.R.China Research Unit of liver cancer Recurrence and Metastasis Chinese Academy of Medical SciencesBeijingP.R.China State Key Laboratory of Medical Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijingP.R.China

Background:Intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic strategies.The metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely unknown.Here,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat iCCA.Methods:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome anal-ysis.Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was determined.Survival and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic subtypes.Cell proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA cells.Results:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were identified.These metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic alterations.The S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)mutations.Among the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)signaling.Conclusion:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing that the S2 subtype exhibited the poorest surviv

关键词： diacylglycerol kinaseα intrahepatic cholangiocarcinoma MAPK signaling metabolic classifi-cation multiomics analysis phosphatidic acid metabolism

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