Pathophysiology and Innovative Therapeutics for ACLF Targeting Necroptosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K23938
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Chiba University
• Principal Investigator: Kondo Takayuki 千葉大学, 医学部附属病院, 助教 (80845090)
• Project Period (FY): 2019-08-30 – 2022-03-31
• Keywords: 慢性肝不全急性増悪 / ACLF / 細胞死 / ネクロプトーシス / RIPK1 / RIPK3 / MLKL / アポローシス

Outline of Final Research Achievements

Acute-on chronic liver failure (ACLF) is an intractable disease with a high mortality rate and no effective treatment options; the pathogenesis of ACLF is primarily characterized by hepatocyte death. Necroptosis is a form of programmed cell death, of which RIPK1, RIPK3, and pMLKL are major components. Therefore, we measured RIPK3 plasma levels and hepatic expression of RIPK1, RIPK3, and pMLKL in ACLF and non-ACLF patients, and investigated the role of necroptosis in ACLF using two animal models of ACLF with inhibitors of RIPK1. The results suggest that necroptosis plays an important role in the pathogenesis of ACLF.

Free Research Field

肝疾患

Academic Significance and Societal Importance of the Research Achievements

これらの研究成果は、ヒトおよび齧歯類のACLFにおいてRIPK1を介したネクロプトーシスと呼ばれる細胞死が重要であることを初めて明らかにした。RIPK1の阻害は、ACLFを発症していない患者からACLFへの進行を防ぐための新規治療アプローチとなる可能性があり、現在有効な治療手段のないACLFの治療手段の一つとなる可能性が示されたため本研究の学術的かつ社会的意義は高いと考えられる。