Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction-associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of disease-associated hepatocytes (daHep) exhibiting enrichment for senescence markers in MASH livers. The emergence of senescent hepatocytes was associated with a marked induction of hepatic thymocyte selection associated (THEMIS) expression in both murine and human MASH. Genetic ablation of Themis, either globally or specifically in hepatocytes, resulted in significant expansion of daHep and senescent hepatocyte populations and exacerbated MASH pathology in mice. Single-nucleus transcriptomic analysis revealed a central role for THEMIS in shaping the cellular landscape of both parenchymal and nonparenchymal compartments within the MASH liver microenvironment. Conversely, adeno-associated virus-mediated overexpression of THEMIS suppressed hepatocyte senescence and attenuated diet-induced MASH. Mechanistic studies revealed that THEMIS deficiency promoted aberrant ERK phosphorylation and hepatocyte senescence. These findings establish THEMIS as a critical hepatoprotective factor that restrains hepatocyte senescence and mitigates metabolic liver disease progression.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by injury to steatotic hepatocytes that triggers the release of endogenous danger-associated molecular patterns. Recent work demonstrated that exposed lipid droplets (LDs) serve as a pathogenic signal that promotes monocyte infiltration and its maturation into triggering receptor expressed in myeloid cells 2 (TREM2+) macrophages in MASH liver. Here we explore the role of LD exposure in modulating inflammatory signaling in macrophages. We found that LD efferocytosis triggers a global transcriptional response and dampens pro-inflammatory signaling in macrophages. LD treatment attenuated NLRP3 inflammasome activation via mechanisms independent of lysosomal LD hydrolysis. While TREM2 was dispensable for LD efferocytosis by macrophages, it was required for the attenuation of proinflammatory signaling upon LD exposure. Additionally, MS4A7 downregulation contributes to LD efferocytosis-mediated dampening of inflammatory response. These results underscore the dual role of LD exposure in MASH liver by promoting monocyte infiltration and TREM2+ macrophage induction, while restraining proinflammatory response in macrophages.

Starvation triggers an organismal adaptive response that is orchestrated by endocrine factors. In this issue of Cell Metabolism, Long et al.1 uncover a famsin-glucagon axis that relays gut-derived hormonal cues to systemic glucose homeostasis during fasting.

Background & Aims: Cellular heterogeneity of innate immune cells, such as macrophages, in the liver is a hallmark of metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis. However, the mechanisms shaping liver macrophage heterogeneity and function during disease progression remain poorly understood. Methods: Control or myeloid-specific Tgfbr1 knockout mice (n = 9-12 per group) were fed a 12-week choline-deficient, amino acid-defined high-fat diet (CDA-HFD) or a 20-week GAN diet (40% fat, 22% fructose, 2% cholesterol). Liver tissue was analyzed using histopathology, quantitative PCR, immunoblotting, flow cytometry, and RNA sequencing (RNA-seq). Bulk RNA-seq (n = 3 per group) and single-nucleus RNA-seq were performed to investigate transcriptional reprogramming. Macrophage population dynamics were evaluated by flow cytometry and immunofluorescence. Results: We identified TGF-β signaling as a crucial regulator of disease-associated expansion of Trem2+ and Fcrl5+ macrophages in MASH livers. Myeloid-specific inactivation of Tgfbr1 in mice exacerbated diet-induced MASH, with increased hepatocyte injury, inflammation, and liver fibrosis. Mechanistically, loss of TGF-β signaling in myeloid cells altered macrophage composition, marked by a reduction in Trem2+ and expansion of Fcrl5+ macrophages. Additionally, macrophages lacking Tgfbr1 exhibited gene signatures associated with inflammasome activation, cytokine signaling, cellular senescence, and immunosuppression. These changes in macrophage composition and function promoted effector T cell exhaustion and the development of MASH-associated hepatocellular carcinoma in Tgfbr1-deficient mice. Conclusions: These findings identify myeloid TGF-β signaling as a key driver of liver macrophage heterogeneity and polarization within the microenvironment during the progression of MASH and MASH-associated liver cancer. Impact and implications: Our study reveals that myeloid TGF-β signaling plays a crucial role in shaping liver macrophage heterogeneity, which in turn influences the pathogenesis of metabolic liver disease. These findings are particularly important for researchers studying immune-metabolic interactions and for clinicians seeking new therapeutic strategies for liver disorders. By elucidating how TGF-β signaling regulates macrophage function, our work paves the way for targeted interventions that modulate immune responses to improve liver health. Future research should consider the potential translational applications of these findings while addressing limitations related to model systems and human variability.

Interorgan crosstalk via secreted hormones and metabolites is a fundamental aspect of mammalian metabolic physiology. Beyond the highly specialized endocrine cells, peripheral tissues are emerging as an important source of metabolic hormones that influence energy and nutrient metabolism and contribute to disease pathogenesis. Neuregulin 4 (Nrg4) is a fat-derived hormone that protects mice from nonalcoholic steatohepatitis (NASH) and NASH-associated liver cancer by shaping hepatic lipid metabolism and the liver immune microenvironment. Despite its enriched expression in brown fat, whether NRG4 plays a role in thermogenic response and mediates the metabolic benefits of cold exposure are areas that remain unexplored. Here we show that Nrg4 expression in inguinal white adipose tissue (iWAT) is highly responsive to chronic cold exposure. Nrg4 deficiency impairs beige fat induction and renders mice more susceptible to diet-induced metabolic disorders under mild cold conditions. Using mice with adipocyte and hepatocyte-specific Nrg4 deletion, we reveal that adipose tissue-derived NRG4, but not hepatic NRG4, is essential for beige fat induction following cold acclimation. Furthermore, treatment with recombinant NRG4-Fc fusion protein promotes beige fat induction in iWAT and improves metabolic health in mice with diet-induced obesity. These findings highlight a critical role of NRG4 in mediating beige fat induction and preserving metabolic health under mild cold conditions.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2(+) macrophages in various disease conditions, and substantial induction of TREM2(+) NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2(+) macrophages in disease pathogenesis.

基于"一种医用接触式皮肤温度测量仪"监测分析中药火灸疗法的温度变化规律,进而评价中药火灸疗法的安全性,为中药火灸疗法的安全运用提供借鉴.方法:纳入94例腰背肌筋膜炎患者,使用测量仪自动测量并显示中药火灸疗法的温度变化,从中提取灭火温度、最高温度、再点火温度、最低温度;观察患者皮肤烫伤及其他不良事件情况;采用视觉模拟评分Visual Analogue Scale(VAS)评估患者火疗后的温度觉感知情况.结果:温度变化规律显示:灭火温度<44℃的烫伤临界温度;最高温度<46℃;最低温度>41℃;再点火温度介于42～44℃之间.无患者出现烫伤及其他不良事件.结论:运用"一种医用接触式皮肤温度测量仪"监测并控制中药火灸疗法的温度不会造成烫伤,其临床运用是安全的.

Nonalcoholic steatohepatitis (NASH) is characterized by persistent liver injury, inflammation, and fibrosis. Myeloid cells, including macrophages and dendritic cells, play an integral role in host defense, tissue homeostasis, and disease progression. Despite this, how myeloid cells contribute to NASH pathogenesis remains obscure. We previously identified NASH-associated macrophages (NAMs) as a unique population of monocyte-derived macrophages in NASH liver. We observed that hepatic NAMs exhibited abundant expression of Brain acid-soluble protein 1 (Basp1), which was markedly induced in the liver upon diet-induced NASH in mice. We generated myeloid-specific Basp1 knockout (Mye-Basp1 KO) mice to determine its role in NASH pathogenesis. Compared to control, Mye-Basp1 KO mice displayed significantly improved liver injury and fibrosis following NASH diet feeding, as shown by lower plasma ALT/AST levels and reduced Sirius Red staining on liver sections, respectively. Hepatocytes from Mye-Basp1 KO mice contained smaller lipid droplets without altering the total liver triglyceride content. Mechanistically, bone marrow-derived macrophages (BMDMs) lacking Basp1 exhibited diminished response to pro-inflammatory stimuli. Importantly, Basp1-deficient BMDMs displayed impaired activation of the NLRP3 inflammasome and secretion of interleukin-1 beta. Together, we propose that Basp1 is a novel regulator of inflammatory signaling in myeloid cells that plays a critical role in NASH pathogenesis. Disclosure Z.Meng: None. L.Zhou: None. S.Hong: None. T.Liu: None. X.Qiu: None. Z.Chen: None. S.Li: None. K.Inoki: None. J.Lin: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK102456)

咳嗽是肺部疾病的常见症状,是中医独立的病证之一 [1],可以清除咽部和整个呼吸道的黏性分泌物、吸入性有害物、异物,对气道的清除作用是有益的 [2-3].另一方面,频繁且剧烈的咳嗽则会对患者的呼吸、心脏功能造成不利影响,若未得到及时有效地治疗,部分患者会发展为咳嗽变异性哮喘 [4].

目的 探讨冯玲教授治疗慢性心力衰竭的用药规律.方法 收集 2016 年 1 月至 2022 年 1 月就诊于中国中医科学院广安门医院冯玲教授门诊有效的慢性心力衰竭病案,运用中医传承计算平台(V3.0),对处方进行药物频次、四气、五味、归经、功效、关联规则分析,挖掘用药规律.使用"处方聚类分析"模块,运用复杂系统熵层次聚类的方法挖掘核心处方.结果 共收集有效处方 1151首,涉及中药 225味.用药频次≥467的中药有 10味,其中黄芪、檀香、桑白皮的频次最高.四气中以寒、温为主,平次之;五味以甘、辛居多,苦次之.归经以入脾、肺、心经为主.药物功效分为理气、补虚、利水渗湿、活血化瘀、化痰止咳平喘等17类.关联规则分析得到 18个关联药对,高频药物聚类分析得到 8 个核心类方,核心方剂组成为黄芪、桑白皮、大腹皮、茯苓、猪苓、丹参、檀香、木香.结论 冯玲教授辨治慢性心衰以气虚血瘀水停为核心病机,治以健脾益气、活血祛瘀、利水消肿为法,"脾肺心"同治,甘辛苦合用.

BACKGROUND AND AIMS:The mammalian liver harbors heterogeneous cell types that communicate via local paracrine signaling. Recent studies have delineated the transcriptomic landscape of the liver in NASH that provides insights into liver cell heterogeneity, intercellular crosstalk, and disease-associated reprogramming. However, the nature of intrahepatic signaling and its role in NASH progression remain obscure. APPROACH AND RESULTS:Here, we performed transcriptomic analyses and identified cardiotrophin-like cytokine factor 1 (CLCF1), a member of the IL-6 family cytokines, as a cholangiocyte-derived paracrine factor that was elevated in the liver from diet-induced NASH mice and patients with NASH. Adenovirus-associated virus-mediated overexpression of CLCF1 in the liver ameliorated NASH pathologies in two diet-induced NASH models in mice, illustrating that CLCF1 induction may serve an adaptive and protective role during NASH pathogenesis. Unexpectedly, messenger RNA and protein levels of leukemia inhibitory factor receptor (LIFR), a subunit of the receptor complex for CLCF1, were markedly downregulated in NASH liver. Hepatocyte-specific inactivation of LIFR accelerated NASH progression in mice, supporting an important role of intrahepatic cytokine signaling in maintaining tissue homeostasis under metabolic stress conditions. CONCLUSIONS:Together, this study sheds light on the molecular nature of intrahepatic paracrine signaling during NASH pathogenesis and uncovers potential targets for therapeutic intervention.

The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as non-alcoholic steatohepatitis (NASH). Patients with NASH are at an increased risk for the development of hepatocellular carcinoma (HCC). However, the mo-lecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis re-mains obscure. Here, we show that diet-induced NASH is characterized by the induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in the liver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this patholog-ical reprogramming during NASH. NRG4 deficiency exacerbated the induction of tumor-prone liver immune microenvironment and NASH-related HCC, whereas transgenic NRG4 overexpression elicited protective ef-fects in mice. In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint.

Introduction: The mortality rate and prognosis factors of short-term and long-term mortality of acute kidney injury (AKI) patients who commence continuous renal replacement therapy (CRRT) are different. Setting up risk stratification tools for both short-term and long-term deaths is of great significance to clinicians.Method: Nine different types of machine learning (ML) algorithms are used to predict mortality risk, including extreme gradient boost (XGBoost), logistic, light gradient boosting machine (LightGBM), randomforest (RF), adaptive boost (AdaBoost), gaussian naive bayes (GausianNB), multi-layer perceptron (MLP), support vector machine (SVC), and k-nearest neighbor (KNN). AUROC, F1-Score, accuracy, sensitivity, specificity, precision, and calibration curve were used for assessing the predictive performance of various ML models.Results: The RF model performed best in both predicting short-term (AUROC: 0.80, 95%CI: 0.74-0.84; Accuracy: 0.72, 95% CI: 0.67-0.76; F1-score: 0.59) and long-term mortality (AUROC: 0.78, 95%CI: 0.73-0.83; Accuracy: 0.73, 95% CI: 0.69-0.78; F1-score: 0.80). The importance of the feature shows that SOFA scores are rated as the most important risk factor for both short-term and long-term mortality.Conclusion: Through machine learning algorithms, our research has realized the risk stratification of death risk in different periods for AKI patients following the initiation of CRRT.

The epidemic situation in 2020 has promoted the development of online education. After the epidemic, in order to make full use of various online education resources, we began to explore online and offline hybrid teaching. In order to improve students' learning interest and enthusiasm, PBL is combined with online and offline teaching mode, and the implementation of teaching mode and teaching effect are introduced.

Exploring key genes associated with non-small cell lung carcinoma (NSCLC) may lead to targeted therapies for NSCLC patients. The protein kinase MAP4K3 has been established as an important modulator of cell growth and autophagy in mammals. Herein, we investigated the somatic mutations and the expression pattern of MAP4K3 detected in NSCLC patients based on the TCGA database. Abnormal MAP4K3 expression and its somatic mutations are associated with the carcinogenesis and thereby becoming an attractive therapeutic target. Baicalein, a natural product, was determined to be the first-reported MAP4K3 binding ligand with its KD values of 6.47 μM measured by microscale thermophoresis. Subsequent in silico docking and mutation studies demonstrated that baicalein directly binds to MAP4K3, presumably to the substrate-binding pocket of this kinase domain, causing inactivity of MAP4K3. We further showed that baicalein could induce degradation of MAP4K3 through decreasing its stability and promoting the ubiquitin proteasome pathway. Degradation of MAP4K3 could cause dissociation of the transcription factor EB and 14-3-3 complex, enhance rapid transport of TFEB to the nucleus and trigger TFEB-dependent autophagy, resulting in lung cancer cells proliferation arrest. Knockdown of MAP4K3 expression by siRNA was sufficient to mimic baicalein-induced autophagy. Ectopic expression of the MAP4K3 protein resulted in significant resistance to baicalein-induced autophagy. Baicalein exhibited good tumor growth inhibition in a nude mouse model for human H1299 xenografts, which might be tightly related to its binding to MAP4K3 and degradation of MAP4K3. Our data provide novel mechanistic insights of baicalein/ MAP4K3/ mTORC1/ TFEB axis in regulating baicalein-induced autophagy in NSCLC, suggesting potential therapies for treatment of NSCLC.

BACKGROUND AND AIMS:Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is characterized by liver injury, inflammation, and fibrosis. NASH pathogenesis is linked to reprogramming of chromatin landscape in the liver that predisposes hepatocytes to stress-induced tissue injury. However, the molecular nature of the putative checkpoint that maintains chromatin architecture and preserves hepatocyte health remains elusive.APPROACH AND RESULTS:Here we show that heterogeneous nuclear ribonucleoprotein U (hnRNPU), a nuclear matrix protein that governs chromatin architecture and gene transcription, is a critical factor that couples chromatin disruption to NASH pathogenesis. RNA-seq and chromatin immunoprecipitation-seq studies revealed an extensive overlap between hnRNPU occupancy and altered gene expression during NASH. Hepatocyte-specific inactivation of hnRNPU disrupted liver chromatin accessibility, activated molecular signature of NASH, and sensitized mice to diet-induced NASH pathogenesis. Mechanistically, hnRNPU deficiency stimulated the expression of a truncated isoform of TrkB (TRKB-T1) that promotes inflammatory signaling in hepatocytes and stress-induced cell death. Brain-derived neurotrophic factor treatment reduced membrane TRKB-T1 protein and protected mice from diet-induced NASH.CONCLUSIONS:These findings illustrate a mechanism through which disruptions of chromatin architecture drive the emergence of disease-specific signaling patterns that promote liver injury and exacerbate NASH pathogenesis.

We uncovered sST2 as an obesity-induced adipokine that exacerbates adipose T reg /ILC2 depletion and promotes insulin resistance.

Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we show that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensable role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility at PPARγ and EBF2 binding sites for key thermogenic genes. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced cold-induced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.

Thermogenesis is an important contributor to whole-body energy expenditure and metabolic homeostasis. Although circulating factors that promote energy expenditure are known, endocrine molecules that suppress energy expenditure have remained largely elusive. Here we found that Tsukushi (TSK) is a liver-enriched secreted factor that is highly inducible in response to increased energy expenditure. Hepatic Tsk expression and plasma TSK levels were elevated in obesity. In mice, TSK deficiency increased sympathetic innervation and norepinephrine release in adipose tissue, leading to enhanced adrenergic signalling and thermogenesis, attenuation of brown fat whitening, and protection from diet-induced obesity. Our data reveal TSK as part of a negative feedback mechanism that gates thermogenic energy expenditure and highlights TSK as a potential target for therapeutic intervention in metabolic disease.

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.