A BCL-xL/BCL-2 PROTAC Effectively Clears Senescent Cells in the Liver and Reduces MASH-driven Hepatocellular Carcinoma in Mice

Overview

Journal Nat Aging

Date 2025 Jan 31

PMID 39890936

Authors

Yang Yang

Natacha Jn-Simon

Yonghan He

Chunbao Sun

Peiyi Zhang

Wanyi Hu

Tian Tian

Huadong Zeng

Sreenivasulu Basha

Araceli S Huerta

Lu-Zhe Sun

Xian-Ming Yin

Robert Hromas

Guangrong Zheng

Liya Pi

Daohong Zhou

Affiliations

Soon will be listed here.

Abstract

Accumulation of senescent cells (SnCs) plays a causative role in many age-related diseases and has also been implicated in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Senolytics that can selectively kill SnCs have the potential to be developed as therapeutics for these diseases. Here we report the finding that 753b, a dual BCL-xL/BCL-2 proteolysis-targeting chimera (PROTAC), acts as a potent and liver-tropic senolytic. We found that treatment with 753b selectively reduced SnCs in the liver in aged mice and STAM mice in part due to its sequestration in the liver. Moreover, 753b treatment could effectively reduce the progression of MASLD and the development of hepatocellular carcinoma (HCC) in STAM mice even after the mice developed substantial metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis. These findings suggest that BCL-xL/BCL-2 PROTACs have the potential to be developed as therapeutics for MASLD to reduce MASH-driven HCC.

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