Journal of hepatology · 2026
Disruption of carbon metabolism by the hepatic mononuclear phagocytic system drives liver injury in a mouse model of severe dengue.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Chen Qian, Yang Wei, Yuan Yi-Zhen, Cai Fang-Zhou, Peng Wan-Jun, Li Zhe, Li Dan, Liu Jiang-Feng, Yang Jun-Tao, Wang Wei
Аннотация
BACKGROUND & AIMS: Severe dengue (SD) is the leading cause of morbidity and mortality resulting from dengue virus (DENV) infection, with liver injury being one of the most common complications. However, besides symptomatic treatment, there is currently no targeted therapy, and the specific mechanism underlying liver injury in SD remains elusive. This study aimed to investigate the molecular mechanisms underlying liver injury in SD to facilitate the development of prophylactic and therapeutic interventions.
METHODS: To systematically characterize dynamic liver lesions in an SD mouse model, we employed multi-omics techniques, including bulk RNA sequencing (RNA-Seq), proteomics, phosphoproteomics, and single-cell RNA sequencing (scRNA-seq). Subsequently, we validated the mRNA and protein expression levels of the screened target molecules by quantitative PCR (qPCR), Western blot (WB), Luminex multiplex assays, and immunofluorescence (IF) assays. To this end, a co-culture system of DENV-infected macrophages and hepatocytes was employed.
RESULTS: Beyond the inflammatory response, multi-omics analysis revealed disruption of carbon metabolism in hepatocytes across multiple time points. Disrupted cell-cell communication between hepatocytes and the hepatic mononuclear phagocytic system (HMPS) contributed to carbon metabolic dysfunction. To elucidate the underlying mechanism, we administered fostamatinib, which effectively inhibited the abnormally activated Bruton's tyrosine kinase (BTK)-mediated signaling pathway in HMPS. This intervention ameliorated carbon metabolism disorders and significantly alleviated liver injury in SD mice.
CONCLUSIONS: Fostamatinib demonstrated significant efficacy in mitigating liver injury induced by DENV infection, while concurrently alleviating inflammatory responses and ameliorating carbon metabolism disorders.
IMPACT AND IMPLICATIONS: Severe dengue, often accompanied by varying degrees of hepatic impairment, constitutes a primary cause of DENV-associated mortality. However, current specific therapeutic interventions remain inadequate. This study demonstrates that the cellular communication between the HMPS and hepatocytes is altered, thereby disrupting carbon metabolic functions in hepatocytes. The administration of fostamatinib ameliorated hepatic carbon metabolic disorders and liver injury. This provides a theoretical foundation for the development of therapeutic interventions targeting hepatic injury in severe dengue.
METHODS: To systematically characterize dynamic liver lesions in an SD mouse model, we employed multi-omics techniques, including bulk RNA sequencing (RNA-Seq), proteomics, phosphoproteomics, and single-cell RNA sequencing (scRNA-seq). Subsequently, we validated the mRNA and protein expression levels of the screened target molecules by quantitative PCR (qPCR), Western blot (WB), Luminex multiplex assays, and immunofluorescence (IF) assays. To this end, a co-culture system of DENV-infected macrophages and hepatocytes was employed.
RESULTS: Beyond the inflammatory response, multi-omics analysis revealed disruption of carbon metabolism in hepatocytes across multiple time points. Disrupted cell-cell communication between hepatocytes and the hepatic mononuclear phagocytic system (HMPS) contributed to carbon metabolic dysfunction. To elucidate the underlying mechanism, we administered fostamatinib, which effectively inhibited the abnormally activated Bruton's tyrosine kinase (BTK)-mediated signaling pathway in HMPS. This intervention ameliorated carbon metabolism disorders and significantly alleviated liver injury in SD mice.
CONCLUSIONS: Fostamatinib demonstrated significant efficacy in mitigating liver injury induced by DENV infection, while concurrently alleviating inflammatory responses and ameliorating carbon metabolism disorders.
IMPACT AND IMPLICATIONS: Severe dengue, often accompanied by varying degrees of hepatic impairment, constitutes a primary cause of DENV-associated mortality. However, current specific therapeutic interventions remain inadequate. This study demonstrates that the cellular communication between the HMPS and hepatocytes is altered, thereby disrupting carbon metabolic functions in hepatocytes. The administration of fostamatinib ameliorated hepatic carbon metabolic disorders and liver injury. This provides a theoretical foundation for the development of therapeutic interventions targeting hepatic injury in severe dengue.