Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic fatty liver disease characterized by lipid accumulation (steatosis), inflammation, and liver fibrosis. MASH could develop to an advanced stage of liver disease, named cirrhosis, which is the leading cause of liver transplantation in developed countries. There is currently only one FAD-approved drug for the MASH treatment due to an incomplete understanding of the pathogenesis of MASH development. In addition, clinical studies have shown that MASH is an independent risk factor for cardiovascular disease (CVD), which is the leading cause of death worldwide.

The Dr. Shi lab is dedicated to uncovering the cellular and molecular mechanisms of MASH pathogenesis, currently focusing on the metabolism of liver macrophages, including liver resident Kupffer cells (KCs) and infiltrated bone marrow-derived macrophages (BMDMs), in clearing the different forms of dead hepatocytes (efferocytosis) during MASH progression and regression. The goal of our study is to discover new potential therapeutics for MASH treatment.

CURRENT PROJECT

Investigating the liver macrophage efferocytosis of dead hepatocyte in MASH

Hepatocyte death is a key feature of MASH, and released intracellular contents (such as ATP and mtDNA) activate hepatic stellate cells (HSCs), causing excessive extracellular matrix (ECM) production and liver fibrosis.  Macrophage efferocytosis of dead hepatocytes reduces intracellular contents from dead hepatocytes, causing less HSC activation. Meanwhile, efferocytotic macrophages reprogram to a pro-resolving phenotype, exhibiting anti-inflammatory / HSC activation through secreting pro-resolving factors and ECM degradation. This project aims to identify the secreted molecules from efferocytotic macrophages using multidisciplinary approaches, including proteomics, RNA sequences, and in vivo/ex vivo experiments. This project is currently funded by the R00 from NIH-NIDDK.

Selected Publications

1. Shi H, Wang X, Li F, Gerlach DB, Yurdagul A, Moore M, Zeldin S, Zhang H, Cai B, Zheng Z, Valenti L, Tabas I. Blocking CD47-SIRPα Signaling Promotes Necroptotic Hepatocyte Engulfment and Improves Experimental Non-alcoholic Steatohepatitis. Science Translational Medicine. 2022 Nov 23;14(672):eabp8309. [PMID: 36417485 PMCID: PMC10199725]
2. Shi H, Wang X, Sloas C, Gerlach DB, Yurdagul A, Moore M, Jung EJ, Mirshahi F, Ronzoni L, Sanyal A, Valenti L, Lin CS, Montgomery J, Zinker B, Klichinsky M, Tabas I. Impaired TIM4-mediated efferocytosis by liver macrophages contributes to liver fibrosis in metabolic dysfunction-associated steatohepatitis. (Science Translational Medicine, under final revision)
3. Shi H, Moore M, Wang X, Tabas I. Efferocytosis in liver disease. JHEP Reports. 2023 Nov 16;6(1):100960. [PMID: 38234410, PMCID: PMC10792655]
4. Wang X, Cai B, Yang X, Sonubi OO, Zheng Z, Ramakrishnan R, Shi H, Valenti L, Pajvani UB, Sandhu J, Infante RE, Radhakrishnan A, Covey DF, Guan K, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I. Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metabolism. 2020; 31(5):969-986. [PMID: 32259482, PMCID: PMC7313619]
5. Wang X, Zeldin S, Shi H, Zhu C, Saito Y, Corey KE, Remotti HE, Verna E, Pajvani UB, Schwabe  RF, Tabas I. TAZ-Induced Cybb in Hepatocytes Contributes to Early Liver Tumorigenesis in Experimental Non-Alcoholic Steatohepatitis. Journal of Hepatology. 2021; 76(4):910-920. [PMID: 34902531, PMCID: PMC8934258]
6. Moore MP, Wang X, Kennelly JP, Shi H, Ishino Y, Kano K, Aoki J, Cherubini A, Ronzoni L, Guo X, Chalasani NP, Khalid S, Saleheen D, Mitsche MA, Rotter JI, Yates KP, Valenti L, Kono N, Tontonoz P, Tabas I. Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation. Hepatology. 2025; 81(2):576-590. [PMID: 38776184, PMCID: PMC11822724]
7. Mederacke I, Filliol A, Affo S, Nair A, Hernandez C, Sun Q, Hamberger F, Brundu F, Chen Y, Ravichandra A, Huebener P, Anke H, Shi H, Martínez García de la Torre RA , Smith JR,  Henderson NC ,  Vondran F, Rothlin CV, Baehre H, Tabas I, Sancho-Bru P, Schwabe RF. The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver. Science Translational Medicine. 2022 Apr 6;14(639):eabe5795. [PMID: 35385339, PMCID: PMC9436006]

Complete List of Published Work in My Bibliography

Principal Investigator
Hongxue Shi, PhD
Assistant Professor of Molecular and Cellular Physiology
hongxue.shi@lsuhs.edu

Yu Jin , PhD
Post-doc Fellow
Email: yu.jin@lsuhs.edu

Postdoctoral Fellows
The Shi lab for MASH disease is currently accepting post-doctoral researchers with a strong background in animal experience, cellular and molecular biology, immunology, and bioinformatic. Interested candidates should review the current research directions and contact Dr. Shi at hongxue.shi@lsuhs.edu for more details.

Graduate Students
The Shi lab for MASH disease has several research projects available for graduate students. Those who are interested should review the current lab research directions and contact Dr. Shi at hongxue.shi@lsuhs.edu for more details.