更新于：2024-11-01

MST2

更新于：2024-11-01

基本信息

别名

hippo (Drosophila) homolog、KRS1、Mammalian STE20-like protein kinase 2

+ [12]

简介

Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38.

关联

项与 MST2 相关的药物

SBP-3264

靶点

MST1 x MST2

作用机制

MST1 inhibitors [+1]

在研机构

Sanford Burnham Prebys Medical Discovery Institute

原研机构

Sanford Burnham Prebys Medical Discovery Institute

在研适应症

急性髓性白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

YL-602

靶点

MST1 x MST2

作用机制

MST1 agonists [+1]

在研机构

四川大学

原研机构

四川大学

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

XMU-MP-1

靶点

MST2 x STK4

作用机制

MST2调节剂 [+1]

在研机构-

原研机构

厦门大学

在研适应症-

非在研适应症

肝损伤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MST2 相关的临床结果

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100 项与 MST2 相关的转化医学

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0 项与 MST2 相关的专利（医药）

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458

项与 MST2 相关的文献（医药）

2024-11-01·Molecular Neurobiology

MST2 Acts via AKT Activity to Promote Neurite Outgrowth and Functional Recovery after Spinal Cord Injury in Mice

Article

作者: Xu, Yi ; Fang, Jiawei ; Wang, Honghai ; Xu, Xu ; Liu, Jinbo ; Zhu, Zhenghuan ; Song, Zhiwen ; Zheng, Hongming

Spinal cord injury (SCI) constitutes a significant clinical challenge, and there is extensive research focused on identifying molecular activities that can facilitate the repair of spinal cord injuries. Mammalian sterile 20-like kinase 2 (MST2), a core component of the Hippo signaling pathway, plays a key role in apoptosis and cell growth. However, its role in neurite outgrowth after spinal cord injury remains unknown. Through comprehensive in vitro and in vivo experiments, we demonstrated that MST2, predominantly expressed in neurons, actively participated in the natural development of the CNS. Post-SCI, MST2 expression significantly increased, indicating its activation and potential role in the early stages of neural recovery. Detailed analyses showed that MST2 knockdown impaired neurite outgrowth and motor function recovery, whereas MST2 overexpression led to the opposite effects, underscoring MST2's neuroprotective role in enhancing neural repair. Further, we elucidated the mechanism underlying MST2's action, revealing its interaction with AKT and positive regulation of AKT activity, a well-established promoter of neurite outgrowth. Notably, MST2's promotion of neurite outgrowth and motor functional recovery was diminished by AKT inhibitors, highlighting the dependency of MST2's neuroprotective effects on AKT signaling. In conclusion, our findings affirmed MST2's pivotal role in fostering neuronal neurite outgrowth and facilitating functional recovery after SCI, mediated through its positive modulation of AKT activity. In conclusion, our findings confirmed MST2's crucial role in neural protection, promoting neurite outgrowth and functional recovery after SCI through positive AKT activity modulation. These results position MST2 as a potential therapeutic target for SCI, offering new insights into strategies for enhancing neuroregeneration and functional restoration.

2024-09-01·The FASEB Journal

YAP activation in liver macrophages via depletion of MST1/MST2 enhances liver inflammation and fibrosis in MASLD

Article

作者: Song, Kejing ; Wu, Tong ; Kolls, Jay ; Song, Kyoungsub ; Zhang, Jinqiang ; Chen, Weina

AbstractMacrophages have been recognized as pivotal players in the progression of MASLD/MASH. However, the molecular mechanisms underlying their multifaceted functions in the disease remain to be further clarified. In the current study, we developed a new mouse model with YAP activation in macrophages to delineate the effect and mechanism of YAP signaling in the pathogenesis of MASLD/MASH. Genetically modified mice, featuring specific depletion of both Mst1 and Mst2 in macrophages/monocytes, were generated and exposed to a high‐fat diet for 12 weeks to induce MASLD. Following this period, livers were collected for histopathological examination, and liver non‐parenchymal cells were isolated and subjected to various analyses, including single‐cell RNA‐sequencing, immunofluorescence and immunoblotting and qRT‐PCR to investigate the impact of YAP signaling on the progression of MASLD. Our data revealed that Mst1/2 depletion in liver macrophages enhanced liver inflammation and fibrosis in MASLD. Using single‐cell RNA‐sequencing, we showed that YAP activation via Mst1/2 depletion upregulated the expressions of both pro‐inflammatory genes and genes associated with resolution/tissue repair. We observed that YAP activation increases Kupffer cell populations (i.e., Kupffer‐2 and Kupffer‐3) which are importantly implicated in the pathogenesis of MASLD/MASH. Our data indicate that YAP activation via Mst1/2 deletion enhances both the pro‐inflammatory and tissue repairing functions of Kupffer‐1 and ‐2 cells at least in part through C1q. These YAP‐regulatory mechanisms control the plasticity of liver macrophages in the context of MASLD/MASH. Our findings provide important evidence supporting the critical regulatory role of YAP signaling in liver macrophage plasticity and the progression of MASLD. Therefore, targeting the Hippo‐YAP pathway may present a promising therapeutic strategy for the treatment of MASH.

2024-07-02·Science Signaling

YAP represses the TEAD–NF-κB complex and inhibits the growth of clear cell renal cell carcinoma

Article

作者: Zhang, Chenmiao ; Zhuang, Ting ; Zhu, Jian ; Xu, Yaning ; Yang, Huijie ; Guo, Haiyang ; Sun, Yanan ; Li, Zhongbo ; Ding, Yinlu ; Su, Peng ; Yang, Penghe ; Jia, Tianwei ; Yu, Miao ; Zhang, Xufeng ; Li, Xin

The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB–target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner—that is, by activating YAP—may be a strategy for slowing tumor growth in patients.

项与 MST2 相关的新闻（医药）

2024-08-19

·微信

Mol Cell | HDACs调控异染色质沉默和表观遗传的分子机制

引言真核生物的细胞核是一个高度有序的场所，首先染色质在细胞核内并非杂乱无章的排列，而是存在于相对特定的区域；其次染色质通常来说可以分为异染色质和常染色质，常染色质因其开放的状态允许转录因子的结合使得基因得以表达，而异染色质由于紧密的核小体组装和相关蛋白的结合阻止了基因的表达。常染色质和兼性异染色质在不同的细胞和发育阶段是可以相互转换的，染色质状态的转换依赖于特定的染色质结合因子的调控，例如Polycomb家族蛋白、组蛋白去乙酰化酶（HDACs）、组蛋白乙酰基转移酶（HATs）和组蛋白甲基转移酶等。Clr3是一种II类HDACs，在酵母的异染色质转录沉默中发挥关键作用。Clr3通过与Snf2形成SHREC复合物，通过HP1依赖和非依赖的机制被导向异染色质，从而选择性地去乙酰化H3K14【1-3】。高水平的Clr3与异染色质结合，防止组蛋白周转（turnover），有助于维持H3K9me3密度阈值，支持异染色质表观遗传抑制的形成【4】。尽管Clr3去乙酰化功能在稳定核小体、引发异染色质转录沉默以及传递表观遗传信息中的重要性已被广泛研究，但是其抑制组蛋白周转的具体机制仍不明确。近日，来自美国国立卫生研究院的Shiv I.S. Grewal在Molecular Cell上发表了论文Nucleosome remodeler exclusion by histone deacetylation enforces heterochromatic silencing and epigenetic inheritance。在本研究中，作者细致的探讨了组蛋白去乙酰化酶、染色质重塑因子、组蛋白甲基转移酶等在调控异染色质稳定性和核小体周转中的作用，其中异染色质区域的高水平HDACs可维持组蛋白低乙酰化，从而确保稳定的基因沉默和表观遗传，但当HDAC功能出现缺陷后，SWI/SNF等重塑因子通过抑制组蛋白甲基转移酶的功能来破坏异染色质的稳定性，改写基因沉默的状态。前期研究发现缺乏Clr3的HDAC活性导致组蛋白周转增加，进而降低H3K9me3水平并影响异染色质的延伸。由于染色质重塑复合物参与核小体的去组装，因此作者推测这些因子可能介导了Clr3缺失导致的异染色质不稳定。为了验证这一推测，作者在clr3D232N缺陷酵母中分别突变了几种重要的染色质重塑因子。研究发现，RSC和SWI/SNF的亚基被突变后，可以恢复由Clr3缺陷导致的基因表达变化，基因沉默得到明显增强，H3K9me3的结合和延伸均恢复至正常状态。这些结果表明，在缺失Clr3去乙酰化酶功能的情况下，RSC和SWI/SNF重塑因子会破坏异染色质的稳定性。接下来，作者研究了Clr3存在的情况下是如何阻止RSC和SWI/SNF重塑因子对异染色质稳定性的破坏。研究结果表明，组蛋白乙酰化可以作为重塑因子的结合信号，促进RSC和SWI/SNF接近异染色质区域，但是当Clr3存在时，它的HDAC活性有效的去除了异染色质区域的组蛋白乙酰化水平，因此阻止了染色质重塑因子对异染色质区域的结合。此外，作者还发现SWI/SNF和RSC对于Clr3缺陷介导的组蛋白周转增加也至关重要。组蛋白乙酰化水平是由HATs和HDACs的活性动态调控的，因此作者进一步研究了HATs在上述发现中的作用。研究发现，将组蛋白乙酰基转移酶Mst2与chromodomain融合表达靶向结合在异染色质区域，可以增强染色质重塑因子对异染色质区域的结合，并且抑制异染色质修饰H3K9me3在Mst2结合区域的延伸。这些结果表明HATs增加了组蛋白乙酰化的水平，从而促进了染色质重塑因子诱导的异染色质不稳定性。为了更加证实SWI/SNF重塑因子的作用，研究人员利用同样的方法将SWI/SNF重塑因子的两个亚基靶向结合在异染色质区域。结果表明，虽然HATs有助于靶向重塑因子以破坏异染色质的稳定性，但这种作用可以通过直接将SWI/SNF靶向结合在异染色质区域而被绕过，SWI/SNF可以破坏核小体的稳定性，从而导致H3K9me3水平和基因沉默的缺失。文章的最后，作者探究了染色质重塑因子是如何影响异染色质的表观遗传和延伸的。通过引入TetR-Clr4（组蛋白甲基转移酶）和CAS序列在异位建立异染色质区域，然后使用Cre-lox系统表达不同形式的SWI/SNF亚基Snf5。研究结果表明，表达靶向异染色质的Snf5会阻碍异染色质的表观遗传信息传播，而这是通过抑制Clr4的读写机制影响了H3K9me3修饰的延伸。模式图（Credit: Molecular Cell）参考文献 1. Sugiyama, T., Cam, H.P., Sugiyama, R., Noma, K., Zofall, M., Kobayashi, R., and Grewal, S.I.S. (2007). SHREC, an effector complex for heterochromatic transcriptional silencing. Cell 128, 491–504. 2. Bjerling, P., Silverstein, R.A., Thon, G., Caudy, A., Grewal, S., and Ekwall, K. (2002). Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity. Mol. Cell. Biol. 22, 2170–2181. 3. Wire ́ n, M., Silverstein, R.A., Sinha, I., Walfridsson, J., Lee, H.M., Laurenson, P., Pillus, L., Robyr, D., Grunstein, M., and Ekwall, K. (2005). Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast. EMBO J. 24, 2906–2918. 4. Ayg€ un, O., Mehta, S., and Grewal, S.I.S. (2013). HDAC-mediated suppression of histone turnover promotes epigenetic stability of heterochromatin. Nat. Struct. Mol. Biol. 20, 547–554. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.molcel.2024.07.006 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-05-21

·Science Daily

Clarifying the cellular mechanisms underlying periodontitis with an improved animal model

Although periodontitis is an extremely prevalent disorder, it is challenging to conduct detailed and comprehensive analyses of its progression at the cellular level. Recently, researchers developed an improved periodontitis mouse model that simplifies the collection and analysis of multiple periodontal tissue types. Using this model, they clarified the role of an important signaling pathway in the inflammatory response of periodontal tissue, paving the way for better diagnostic and therapeutic strategies for periodontitis. Periodontal disease, represented by periodontitis, is the leading cause of tooth loss and affects close to one in five adults worldwide. In most cases, this condition occurs as a result of an inflammatory response to bacterial infection of the tissue around teeth. As the condition worsens, the gums begin to pull away, exposing teeth roots and bone. Notably, the incidence of periodontitis becomes more prevalent with age and with populations worldwide living longer, developing a solid understanding of its underlying causes and progression is important. In a study recently published in Nature Communications on March 28, 2024, researchers from Tokyo Medical and Dental University (TMDU) found a way to achieve this by improving upon a widely used animal model to study periodontitis. Studying periodontitis directly in humans is challenging. As a result, scientists often resort to animal models for preclinical research. For instance, the "mouse ligature-induced periodontitis model," since its inception in 2012, has enabled researchers to study the cellular mechanisms underlying this condition. Simply put, with this model, periodontal disease is artificially induced by ligating silk threads onto the molars of mice models, which induces plaque accumulation. While convenient and effective, this model, however, fails to capture the complete picture of periodontitis. "Even though the periodontal tissue is composed of gingiva, periodontal ligament, alveolar bone, and cementum, analyses are usually performed exclusively on gingival samples due to technical and quantitative limitations," remarks lead author Mr. Anhao Liu. "This sampling strategy limits the conclusions that may be drawn from these studies, so methods that allow for the simultaneous analysis of all tissue components are needed." To address this limitation, the research team developed a modified ligature-induced periodontitis model. Instead of the classic single ligature, they used a triple ligature approach on the upper left molar of male mice. This strategy expanded the range of bone loss without causing severe bone destruction around the second molar, increasing the yield of the different types of periodontal tissue. "We isolated the three main tissue types and evaluated the RNA yield between the two models. The results showed that the triple-ligature model effectively increased the yield, achieving four times the yield of normal peri-root tissue and supporting the high-resolution analysis of different tissue types," explains senior author Dr. Mikihito Hayashi. After confirming the efficacy of their modified model, the researchers proceeded to investigate the effects of periodontitis on gene expression among the different tissue types over time, focusing on genes related to inflammation and osteoclast differentiation. One of their main findings was that the expression of the Il1rl1 gene was markedly higher in peri-root tissue five days after ligation. This gene encodes the protein ST2 in both receptor and decoy isoform, which binds to a cytokine called IL-33 that is involved in inflammatory and immunoregulation processes. To gain further insights into the role of this gene, the team induced periodontitis in genetically modified mice that lacked the Il1rl1 or Il33 genes. These mice exhibited accelerated inflammatory bone destruction, highlighting the protective role of the IL-33/ST2 pathway. Further analysis of cells containing the ST2 protein in its receptor form, mST2, revealed that most of them were of macrophage lineage. "Macrophages are typically classified into two main types, pro-inflammatory and anti-inflammatory, based on their activation process. We found that mST2-expressing cells were unique in that they expressed some markers of both types of macrophages simultaneously," comments senior author Dr. Takanori Iwata. "These cells were present in the peri-root tissue before inflammation was triggered, so we named them 'periodontal tissue-resident macrophages.'" Together, the findings of this study showcase the power of this modified animal model to study the full scope of periodontitis in greater detail, right down to the biomolecular level. "We suggest the possibility that a novel IL-33/ST2 molecular pathway regulating inflammation and bone destruction in periodontal disease, alongside specific macrophages in peri-root tissue, is deeply involved in periodontal disease. This will hopefully lead to the development of new treatment strategies and prevention methods," concludes senior author Dr. Tomoki Nakashima.

2023-03-24

·生物谷

南方科技大学王艺瑾团队发表感染及肝脏疾病线粒体稳态系列研究成果

炎症过激活是脓毒症器官损伤发生的决定因素。心肌收缩和松弛是消耗能量的过程，高度依赖线粒体ATP供应。线粒体质量控制(mitochondrial quality control，MQC) 是一种细胞内源性保护程序，用于维持线粒体稳态。该系统调节线粒体分裂/融合，线粒体自噬和生物发生，以修复或去除结构不良的线粒体，从而维持线粒体功能和ATP的产生。增加融合或减少分裂可减少碎片线粒体的形成，同时线粒体自噬有助于消除无法修复的细胞器。尽管在脓毒性心肌病 (SCM) 中观察到线粒体损伤，但相关的MQC功能障碍和调节机制仍不清楚。2023年1月，王艺瑾团队在Metabolism-Clinical and Experimental (中科院一区)发表题为TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury的研究论文。作者构建了心肌细胞特异性TMBIM6敲除小鼠 (TMBIM6CKO) 和TMBIM6转基因小鼠 (TMBIM6TG)，揭示了TMBIM6-VDAC1相互作用可以阻止VDAC1寡聚化，从而维持体内线粒体Ca2+平衡以及正常的MQC过程，有助于改善SCM的心肌功能。本研究揭示了TMBIM6在脓毒症中通过维持[Ca2+]m稳态，从而改善心肌细胞中的线粒体动态平衡，为进一步了解脓毒症相关线粒体功能障碍的分子机制提供了新的见解。预防脓毒症相关TMBIM6下调的策略可能有助于通过保留VDAC1单体构象状态来缓解脓毒症诱导的心肌损伤。文章链接：https://www-sciencedirect-com.libproxy1.nus.edu.sg/science/article/pii/S002604952200261X丝氨酸/苏氨酸激酶3（STK3），也被称为哺乳动物无菌20样激酶1（Mst1），是影响细胞凋亡和氧化应激的Hippo途径的核心成分。STK3的几个底物已被报道，包括GULT1、MAPK、NLRP3、LTB4、SAV1等。以前的研究结果主要阐明了STK3在多种心血管疾病下的病理作用，如糖尿病心肌病、儿茶酚胺诱发的心肌病、以及应激性心肌肥大。然而，STK3在脓毒症心肌病中的作用未见报道。2023年3月，王艺瑾团队在Int J Biol Sci上发表题为Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation的研究论文。作者构建了STK3敲除小鼠 (STK3-/-)，揭示了STK3过度表达通过直接结合KEAP1并诱发其磷酸化，继而干扰KEAP1入核转位并由此下调Nrf2的转录，从而造成线粒体氧化应激损伤，最终扩大脓毒症条件下的心功能障碍。阻止STK3上调、逆转KEAP1磷酸化、增强Nrf2转录的手段和药物，可能是预防或治疗脓毒症心肌病的关键手段。文章链接：https://www.ijbs.com/v19p1369.htm酒精性肝病(ALD)的特征是过量饮酒导致肝组织病变。ALD的唯一有效治疗方法是戒酒，但这对酒精性肝硬化患者的预后没有显著改善。探究酒精性肝损伤分子机制可为ALD的防治提供新的途径。2023年3月，王艺瑾团队在Int J Biol Sci 上发表题为“Interaction between dual specificity phosphatase-1 and cullin-1 attenuates alcohol-related liver disease by restoring p62-mediated mitophagy”的研究论文。本文发现DUSP1下调是ALD发生的初始信号，DUSP1通过抑制线粒体自噬而导致线粒体功能障碍。在生理条件下，DUSP1与胞浆中的CUL1结合，阻止其易位到细胞核。酒精暴露后，DUSP1的表达减少，导致CUL1解离并穿梭到细胞核中，作为转录抑制物抑制Parkin和p62的表达。后者与线粒体自噬受损有关，并损害ATP的生成。通过DUSP1过表达或CUL1缺失来恢复线粒体自噬功能可以极大地减轻ALD肝细胞线粒体功能障碍。文章链接：https://www.ijbs.com/v19p1831.htm肝脏疾病是全球患者死亡的重要原因。线粒体功能障碍与多种急慢性肝病相关。线粒体自噬可以选择性地降解受损线粒体，维持线粒体网络功能的完整性和细胞稳态。在生理状态下，线粒体自噬起到保护肝脏免受组织损伤、维持肝脏稳态的作用。而线粒自噬受损或过激活在肝病发病机制中起重要作用。线粒体自噬介导的线粒体降解途径、线粒体自噬在肝脏疾病中的稳态失衡以及改变线粒体自噬是否可以作为肝脏病治疗靶点已有广泛研究。2023年3月，王艺瑾团队在Antioxidants & Redox Signaling发表题为“The Role and Mechanism of Action of Mitophagy in Various Liver Diseases”的长篇综述，总结了线粒体自噬在各种肝脏疾病中的作用以及以线粒体自噬为靶点的潜在的治疗方案，对肝脏疾病发病机制及治疗具有重要意义。文章链接：https://www-liebertpub-com.libproxy1.nus.edu.sg/doi/epub/10.1089/ars.2022.0114通讯作者简介：王艺瑾南方科技大学医学院副教授，博士生导师深圳市海外高层次人才北京市科技新星计划获得者欧洲肝病学会青年科学奖获得者中国戊型肝炎研究协作组(CCSHE)组长中国研究型医院学会肝病专委会青年委员会副主委以第一/通讯作者在国际学术期刊Lancet RM, Science Advances, Gastroenterology, Hepatology, Journal of Hepatology, Medicine, EBioMedicine发表论文多篇，他引7000余次，入选2022全球前2%顶尖科学家榜单。研究领域：1、肝炎病毒-宿主互作、抗病毒天然免疫机制及策略2、脓毒症发病机制3、线粒体稳态在感染及谢性疾病中的调控机制4、脂肪肝发病机制5、肝脏肿瘤