American Journal of Pathology最新文献_第6页

Microglia Promote Neurodegeneration and Hyperkatifeia during Withdrawal and Abstinence from Binge Alcohol 小胶质细胞促进神经变性和酗酒戒断期间过度兴奋。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-11-01 DOI: 10.1016/j.ajpath.2025.10.005

Elizabeth M. McNair , Lamar W. Dawkins , Baylee Materia , Grace Ross , Alexandra Barnett , Puja Nakkala , Liya Qin , Jian Zou , Viktoriya Nikolova , Sheryl Moy , Leon G. Coleman Jr.

Proinflammatory microglial polarization, neuronal death, and hyperkatifeia/negative affect during withdrawal are key features of alcohol use disorder (AUD). However, the role microglia play in the development of AUD-related neuronal and behavioral pathology is unclear. Given the ability of microglia to impact neuronal function, it was hypothesized that proinflammatory microglia promote neuronal death and hyperkatifeia during prolonged abstinence from binge alcohol. Proinflammatory signaling and affective state were assessed in mice either during acute withdrawal (24 hours) or abstinence (>4 weeks) to binge alcohol exposure. Ten days of binge alcohol increased proinflammatory gene signaling 24 hours after ethanol, which lasted weeks into withdrawal. Alcohol reduced brain-derived neurotrophic factor in hyperkatifeia-associated regions (ie, the central amygdala and infralimbic cortex) during acute withdrawal and caused persistent microglial structural changes and loss of microglial brain-derived neurotrophic factor in the bed nucleus of the stria terminalis during abstinence. This was associated with increased anxiety-like behavior and hyperarousal, with persistent enhancement of conditioned fear memory during abstinence. Inhibition of proinflammatory microglia with Gi designer receptors exclusively activated by designer drugs blocked neuronal death and prevented persistent proinflammatory gene induction and hyperkatifeia in female mice. Thus, this identifies a direct role for microglia in the development of AUD-related neuropathology and behavioral dysfunction, implicating microglia as cellular targets for the prevention of AUD phenotypes.

促炎小胶质细胞极化、神经元死亡和戒断期间的过度兴奋/负面影响是酒精使用障碍（AUD）的主要特征。然而，小胶质细胞在aud相关神经元和行为病理发展中的作用尚不清楚。考虑到小胶质细胞影响神经元功能的能力，我们假设促炎小胶质细胞在长期戒酒期间促进神经元死亡和过度饮酒。在小鼠急性戒断（24小时）或戒断（4周）期间，对狂饮酒精暴露的促炎信号和情感状态进行评估。10天的狂饮会在EtOH后24小时增加促炎基因信号，持续数周直至停药。在急性戒断期间，酒精降低了高katifeia相关区域（即中央杏仁核和边缘下皮层）的脑源性神经营养因子（BDNF），并导致戒断期间BNST中持续的小胶质结构改变和小胶质BDNF的丧失。这与增加的焦虑样行为和过度觉醒有关，在禁欲期间持续增强条件性恐惧记忆。用设计药物（DREADDs）激活的Gi设计受体抑制雌性小鼠的促炎小胶质细胞，可阻断神经元死亡，防止持续的促炎基因诱导和过度兴奋。因此，这确定了小胶质细胞在AUD相关神经病理学和行为功能障碍发展中的直接作用，暗示小胶质细胞是预防AUD表型的细胞靶点。

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引用次数: 0

Liver Macrophage Changes during Early Adaptation to Alcohol Exposure 肝巨噬细胞在酒精暴露的早期适应过程中的变化。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-31 DOI: 10.1016/j.ajpath.2025.10.004

Kyle Yuquimpo , Janice Averilla , Zhuan Li , Priyanka Ghosh , Sheetalnath Rooge , Isabel A. Pulido Ruiz , Winston Dunn , Sumedha Gunewardena , Ann L. Wozniak , Irina Tikhanovich , Steven A. Weinman

Liver macrophages consist of both Kupffer cells (KCs) and infiltrating macrophages (IMs), and both populations change during alcohol-associated liver disease. It has been suggested that KCs undergo a proinflammatory change after alcohol exposure, but the extent to which a proinflammatory shift results from IM rather than KC activation is unclear. The purpose of this study was to examine the early effects of alcohol exposure on KCs and IMs in a murine model and compare these effects with observations in human liver. Mice were fed the Lieber-Decarli ethanol diet, and total liver macrophage and KC-specific phenotypes were examined by flow cytometry, ex vivo cell culture, and KC single-cell RNA sequencing. Liver tissues from autopsy and transplant patients with different alcohol phenotypes were assessed. Early alcohol exposure caused a shift in the properties of total liver macrophages, with an initial proinflammatory effect that partially resolved by 10 days. KCs became steadily less inflammatory over the first 10 days of alcohol exposure. Alcohol exposure in the absence of liver disease also shifted macrophage phenotypes in human livers. These results show that early alcohol exposure is sufficient to cause KC adaptation in a way that maintains liver homeostasis and limits inflammation. Understanding the mechanisms of these changes and how to sustain them may help prevent the development of long-term liver injury.

肝巨噬细胞包括库普弗细胞（KCs）和浸润性巨噬细胞（IM），两者在酒精相关性肝病期间发生变化。有人认为，酒精暴露后KCs会发生促炎变化，但促炎变化在多大程度上是由IMs而不是KC激活引起的尚不清楚。本研究的目的是在小鼠模型中检查酒精暴露对KCs和IMs的早期影响，并将这些影响与人类肝脏中的观察结果进行比较。小鼠分别饲喂Lieber-Decarli乙醇饲料和总肝巨噬细胞，通过流式细胞术、离体细胞培养和KC单细胞RNAseq检测KC特异性表型。对不同酒精表型的尸检和移植患者的肝组织进行了评估。早期酒精暴露导致总肝巨噬细胞性质的改变，具有最初的促炎作用，10天后部分消退。在酒精暴露的前10天，KCs的炎症性逐渐减弱。在没有肝脏疾病的情况下，酒精暴露也会改变人类肝脏中的巨噬细胞表型。这些结果表明，早期酒精暴露足以以维持肝脏稳态和限制炎症的方式引起KC适应。了解这些变化的机制以及如何维持它们可能有助于预防长期肝损伤的发展。

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引用次数: 0

A Century of Progress Toward Gut Barrier Targeting Therapies in Inflammatory Diseases 炎症性疾病肠道屏障靶向治疗的一个世纪进展

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.04.021

Manuel B. Braga-Neto , Andrei I. Ivanov

引用次数: 0

Advancing Breast Cancer Management Through an Enhanced Understanding of Disease Heterogeneity from Initiation to Metastasis 通过加深对从发病到转移的疾病异质性的了解来推进乳腺癌的管理

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.08.003

Dennis Jones

引用次数: 0

Novel Insights into Neurodegenerative Diseases 神经退行性疾病的新见解

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.09.002

Steven L. Carroll, Jody Fromm Longo

引用次数: 0

Prostaglandin E2 Signaling Triggers CD31-Independent Transendothelial Migration in Vitro and in Vivo PGE2信号在体外和体内触发cd31不依赖的跨内皮迁移。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-17 DOI: 10.1016/j.ajpath.2025.09.012

Vanessa Hayashi , Michael A. Seidman , William A. Muller

Genetic deletion or antibody blockade of platelet endothelial cell adhesion molecule-1 (PECAM; CD31) inhibits transendothelial migration (TEM) of leukocytes in all mouse strains studied except C57BL/6. A prior publication showed that this phenotype maps to a single 35.8-Mb locus on mouse chromosome 2, that contains the genes Ptgs1, Ptges, and Ptges2, which encode key enzymes involved in the prostaglandin E₂ (PGE₂) synthesis pathway. PGE₂ is a proinflammatory lipid mediator that binds four E prostanoid receptors (EPs 1 to 4). It was hypothesized that PGE₂ signaling supports TEM via a CD31-independent mechanism. In vitro TEM assays demonstrate that PGE₂ or 16,16-dimethyl PGE₂ can restore transmigration of polymorphonuclear leukocytes and peripheral blood mononuclear cells despite a TEM blockade with anti-CD31. This protransmigratory effect could be blocked with the EP1 antagonist, SC-51089, or with transient receptor potential canonical 6 antagonist, BI-749327. 17-Phenyl trinor PGE₂, an agonist of EP1 and EP3, also restored transmigration of polymorphonuclear leukocytes blocked with anti-CD31. In vivo, PGE₂ overcame an anti-CD31 blockade when administered to FVB/n mice in thioglycolate peritonitis or croton oil dermatitis models, whereas blocking EP1 with SC-51089 decreased TEM in C57BL/6 pecam1^−/− mice. The findings support earlier data that identified PGE₂ as a candidate inducer of CD31-independent TEM, and pinpoint EP1 as the receptor that relays that signal to activate transient receptor potential canonical 6.

基因缺失或抗体阻断血小板内皮细胞粘附分子-1 （CD31， PECAM）可抑制除C57BL/6外所有小鼠品系白细胞的跨内皮迁移（TEM）。先前的一项研究表明，这种表型映射到小鼠2号染色体上一个35.8 Mb的位点，该位点包含基因Ptgs1， Ptges和Ptges2，这些基因编码参与前列腺素E2 （PGE2）合成途径的关键酶。PGE2是一种促炎脂质介质，可结合四种E前列腺素受体（EP1-4）。假设PGE2信号通过不依赖cd31的机制支持TEM。体外透射电镜分析表明，PGE2或16,16-二甲基PGE2可以恢复多形核白细胞（PMNs）和外周血单核细胞（PBMCs）的转运，尽管有抗cd31的透射电镜阻断。EP1拮抗剂SC-51089或瞬时受体电位规范6 （TRPC6）拮抗剂BI-749327可阻断这种促迁移作用。17-苯基三甲基PGE2是EP1和EP3的激动剂，也能恢复被抗cd31阻断的PMNs的转运。体内实验结果显示，巯基乙酸腹膜炎或巴豆油皮炎模型的FVB/n小鼠中，PGE2克服了抗cd31阻滞，而用SC-51089阻断EP1可降低C57BL/6 pecam1-/-小鼠的TEM。这些发现支持了先前的数据，即PGE2是cd31非依赖性TEM的候选诱导剂，并确定EP1是传递该信号以激活TRPC6的受体。

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引用次数: 0

Specialized Pro-Resolving Mediators MaR1 and LXA4 Resolve Inflammation During Acute Chemical Lung Injury in the Absence of Neutrophils 特殊的促溶解介质MaR1和LXA4可在中性粒细胞缺乏的急性化学性肺损伤中缓解炎症。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.013

Maureen E. Haynes, Vivienne Fang, Meital Gewirtz, David P. Sullivan, William A. Muller

Gastric aspiration pneumonia involves chemical injury to the alveoli of the lungs with inflammation, tissue damage, and recruitment of polymorphonuclear leukocytes (PMNs). PMNs are also known to be involved in the production of specialized pro-resolving mediators (SPMs), small lipid molecules that contribute to the resolution of inflammation. This study aimed to identify target PMN-produced SPMs and interrogate their actions and potential use for therapeutic treatment after chemical injury. The data revealed that maresin 1 (MaR1), lipoxin A₄, and 18-HEPE are produced after chemical injury in the lungs, and that exogenous treatment with these SPMs reduces the acute influx of PMNs into the airspace. In a chemical lung injury model in which neutropenic mice all die within 48 hours, treatment with MaR1 or LXA₄ rescued survival of neutropenic mice to the levels of immunologically intact mice, and reduced CD11b expression, a proinflammatory marker, on recruited PMNs. Exogenous treatment with MaR1 or LXA₄ reduced the concentration of proinflammatory cytokines TNF⍺, IL6, and MCP-1 in the airspace at 24 hours after injury. These data show that exogenous treatment with MaR1 or LXA₄ ameliorates acute inflammation after chemical lung injury and contributes to survival of severe murine aspiration pneumonia in neutropenic animals. These data have implications for treatment of sterile lung injury in immunocompromised patients.

胃吸入性肺炎涉及肺部肺泡的化学损伤，伴有炎症、组织损伤和多形核白细胞（pmn）的募集。pmn还参与产生专门的促溶解介质（SPMs），这是一种有助于炎症消退的小脂质分子。本研究旨在确定目标pmn产生的SPMs，并探讨它们在化学损伤后的作用和潜在的治疗用途。我们的数据显示，肺化学损伤后产生Maresin 1 （MaR1; 7R， 14s -二羟基-二十二酸- 4z，8E,10E,12Z,16Z， 19z -己酸），Lipoxin A4 （LXA4, 5S,6R， 15s -三羟基- 7e，9E,11Z， 13e -二十碳四烯酸）和18-HEPE（（±）-18-羟基- 5z，8Z,11Z,14Z， 16e -二十碳五烯酸），外源性处理这些SPMs可减少PMNs急性流入空气中。在化学肺损伤模型中，中性粒细胞减少小鼠在48小时内全部死亡，用MaR1或LXA4治疗使中性粒细胞减少小鼠的存活恢复到免疫完整小鼠的水平，并降低募集PMNs上促炎标志物CD11b的表达。用MaR1或LXA4外源性处理可在损伤后24小时降低空气中促炎细胞因子TNF、IL6和MCP-1的浓度。这些数据表明，用MaR1或LXA4外源性治疗可改善化学肺损伤后的急性炎症，并有助于中性粒细胞减少动物的严重小鼠吸入性肺炎的存活。这些数据对免疫功能低下患者无菌性肺损伤的治疗具有启示意义。

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引用次数: 0

Improving Colorectal Cancer Screening and Risk Assessment through Predictive Modeling on Medical Images and Records 基于医学影像和记录的预测建模改进结直肠癌筛查和风险评估。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.016

Shuai Jiang , Christina Robinson , Joseph Anderson , William Hisey , Lynn Butterly , Arief Suriawinata , Saeed Hassanpour

Colonoscopy screening effectively identifies and removes polyps before they progress to colorectal cancer (CRC), but current follow-up guidelines rely primarily on histopathologic features, overlooking other important CRC risk factors. Variability in polyp characterization among pathologists also hinders consistent surveillance decisions. Advances in digital pathology and deep learning enable the integration of pathology slides and medical records for more accurate progression risk prediction. Using data from the New Hampshire Colonoscopy Registry, including longitudinal follow-up, a transformer-based model for histopathology image analysis was adapted to predict 5-year progression risk. Multi-modal fusion strategies were further explored to combine clinical records with deep learning–derived image features. Training the model to predict intermediate clinical variables improved 5-year progression risk prediction [area under the receiver-operating characteristic curve (AUC), 0.630] compared with direct prediction (AUC, 0.615; P = 0.013). Integrating whole-slide imaging–based model predictions with nonimaging features further improved performance (AUC, 0.672), significantly outperforming the nonimaging-only approach (AUC, 0.666; P = 0.002). These results highlight the value of integrating diverse data modalities with computational methods to enhance progression risk stratification.

结肠镜筛查可以有效地在息肉发展为结直肠癌（CRC）之前识别并切除息肉，但目前的随访指南主要依赖于组织病理学特征，忽略了其他重要的CRC危险因素。病理学家之间息肉特征的差异也阻碍了一致的监测决策。数字病理学和深度学习的进步使病理切片和医疗记录的整合能够更准确地预测进展风险。利用新罕布什尔结肠镜登记中心的数据，包括纵向随访，采用基于变压器的组织病理学图像分析模型来预测5年进展风险。进一步探索多模式融合策略，将临床记录与深度学习衍生的图像特征相结合。与直接预测（AUC = 0.615, p = 0.013）相比，训练模型预测中间临床变量可提高5年进展风险预测（AUC = 0.630）。将基于wsi的模型预测与非成像特征相结合进一步提高了性能（AUC = 0.672），显著优于仅非成像方法（AUC = 0.666, p = 0.002）。这些结果强调了将不同数据模式与计算方法相结合以增强进展风险分层的价值。

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引用次数: 0

Inactivation of Atp7b Copper Transporter in Intestinal Epithelial Cells Is Associated with Altered Lipid Processing and Cell Growth Machinery Independent from Hepatic Copper Accumulation and Severity of Liver Histology 肠上皮细胞中Atp7b铜转运体的失活与脂质加工和细胞生长机制的改变有关，与肝铜积累和肝脏组织学的严重程度无关。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.015

Amanda Caceres , Noreene M. Shibata , Christian D. Davalos-Gutierrez , Gaurav V. Sarode , Hisham Hussan , Margarida Bettencourt , Adriana Fontes , Hans Zischka , Svetlana Lutsenko , Marie C. Heffern , Valentina Medici

The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and brain, but little is known about the role of other organs expressing the ATP7B copper transporter on metabolic and ultrastructural changes characterizing WD. To examine the consequences of intestinal Atp7b inactivation in the absence of hepatic copper accumulation, a new mouse model (Atp7b^ΔIEC) characterized by enterocyte-specific Atp7b inactivation was generated. Atp7b^ΔIEC mice were compared with wild-type mice with the same genetic background (iWT). The Atp7b global knockout (Atp7b^–/–) model of WD on a C57Bl/6 background was previously generated and compared with its respective wild type (WT). Hepatic copper, lipid metabolism, liver and intestine histology, and electron microscopy were assessed over time up to 30 weeks of age. Although there was no evidence of intestine copper accumulation in Atp7b^ΔIEC mice, transcriptome analysis in Atp7b^ΔIEC mice revealed changes in genes involved in AMP-activated protein kinase signaling, fatty acid metabolism, and cell cycle both with partial overlap between the intestinal epithelial cells and the liver. Mitochondrial and other ultrastructural changes were observed in the intestinal epithelial cells of both Atp7b^–/– and Atp7b^ΔIEC mice. Intestine-specific Atp7b deficit affects systemic metabolic pathways and intestine morphology, and hepatic metabolic perturbations are associated with intestinal dysfunction, independently from hepatic copper accumulation, providing evidence that the WD phenotype is at least partially influenced by organ-specific ATP7B variants.

Wilson病（WD）的临床表现与铜在肝脏和大脑的积累有关，但对其他器官表达ATP7B铜转运体在WD代谢和超微结构变化中的作用知之甚少。为了研究在没有肝铜积累的情况下肠道Atp7b失活的后果，我们建立了一个以肠细胞特异性Atp7b失活为特征的新小鼠模型（Atp7bΔIEC）。将Atp7bΔIEC小鼠与具有相同遗传背景（iWT）的野生型小鼠进行比较。在C57Bl/6背景下，WD的Atp7b全基因敲除（Atp7b-/-）模型之前已被生成，并与各自的WT进行了比较。肝铜、脂质代谢、肝脏和肠道组织学以及电子显微镜在30周龄时进行了评估。虽然在Atp7bΔIEC小鼠中没有肠道铜积累的证据，但在Atp7bΔIEC小鼠中进行的转录组分析显示，参与AMPK信号、脂肪酸代谢和细胞周期的基因发生了变化，并且在肠上皮细胞和肝脏之间存在部分重叠。Atp7b-/-和Atp7bΔIEC小鼠肠上皮细胞均观察到线粒体和其他超微结构的改变。肠道特异性Atp7b缺陷影响全身代谢途径和肠道形态，肝脏代谢紊乱与肠道功能障碍相关，独立于肝铜积累，提供了WD表型至少部分受器官特异性Atp7b变异影响的证据。

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引用次数: 0

Transforming Growth Factor-β Signaling in Alcohol-Associated Liver Disease 转化生长因子-β信号在酒精相关肝病中的作用：多细胞视角

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.017

Huihui Zou , Sai Wang , Chenjun Huang , Steven Dooley , Nadja M. Meindl-Beinker

Transforming growth factor-β (TGF-β) signaling exerts broad regulatory effects on alcohol-associated liver disease (ALD) progression, influencing processes such as hepatocellular injury, regeneration, inflammation, fibrogenesis, cirrhosis, carcinogenesis, and hepatic failure. TGF-β modifies alcohol-induced signals in multiple liver-resident cell types, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells, and immune populations, particularly macrophages. To delineate its context-specific roles in ALD, 154 of 421 PubMed-listed publications (2000 to 2025; search terms TGF-β and alcohol and liver disease) were reviewed, supplemented by 19 foundational studies published earlier. In hepatocytes, TGF-β promotes oxidative stress, apoptosis, metabolic reprogramming, and epithelial-to-mesenchymal transition. In hepatic stellate cells and Kupffer cells, gut-derived endotoxins, ethanol, and unsaturated fatty acids induce TGF-β alongside proinflammatory cytokines. Ethanol metabolism generates acetaldehyde, which drives TGF-β and receptor expression, enhances canonical and noncanonical signaling, and engages epigenetic regulators to promote extracellular matrix deposition. In liver sinusoidal endothelial cells, alcohol-induced TGF-β suppresses proliferation, contributing to sinusoidal capillarization, impaired endothelial regeneration, and fibrogenesis. TGF-β dampens clearance of damaged hepatocytes and perpetuating chronic injury by suppressing natural killer cell cytotoxicity and promoting regulatory T-cell differentiation. At end-stage disease, TGF-β promotes expansion and fate switching of cholangiocyte-derived liver progenitor cells to replenish lost hepatocytes. Despite its central role in ALD, therapeutic exploitation of TGF-β signaling remains underexplored. Future studies should define cell type–specific signaling nodes to enable precision therapies.

转化生长因子-β (TGF-β)信号在酒精相关性肝病（ALD）进展中发挥广泛的调节作用，影响肝细胞损伤、再生、炎症、纤维化、肝硬化、癌变和肝功能衰竭等过程。TGF-β改变多种肝驻留细胞类型中酒精诱导的信号，包括肝细胞、肝星状细胞（hsc）、肝窦内皮细胞（LSECs）和免疫群体，特别是巨噬细胞。为了描述其在ALD中的具体作用，我们回顾了421篇pubmed列出的出版物中的172篇（2000年至2025年，搜索词“TGF-β”和“酒精”和“肝脏疾病”），并补充了之前发表的18篇基础研究。在肝细胞中，TGF-β促进氧化应激、细胞凋亡、代谢重编程和上皮到间质转化。在造血干细胞和库普弗细胞（KCs）中，肠道来源的内毒素、乙醇和不饱和脂肪酸与促炎细胞因子一起诱导TGF-β。乙醇代谢产生乙醛，驱动TGF-β和受体表达，增强典型和非典型信号传导，并参与表观遗传调节因子促进细胞外基质沉积。在LSECs中，酒精诱导的TGF-β抑制增殖，促进窦状毛细血管形成，内皮再生受损和纤维形成。TGF-β通过抑制自然杀伤细胞的细胞毒性和促进调节性T细胞分化，抑制受损肝细胞的清除和慢性损伤的延续。在终末期疾病中，TGF-β促进胆管细胞来源的肝祖细胞的扩张和命运转换，以补充失去的肝细胞。尽管TGF-β在ALD中发挥核心作用，但TGF-β信号的治疗利用仍未得到充分探索。未来的研究应确定细胞类型特异性信号节点，以实现精确治疗。

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引用次数: 0