Congratulations to Daohong Zhou, MD and his team on their publication in Nature Aging!
The manuscript, “A BCL-xL/BCL-2 PROTAC effectively clears senescent cells in the liver and reduces MASH-driven hepatocellular carcinoma in mice,” was published in Nature Aging. In the paper, they reported the discovery of the first liver tropic senolytic BCL-xL and BCL-2 PROTAC 753b, which can selectively reduce senescent cells in the liver in aged mice and STAM mice (an NAFLD/MASLD animal model) in part due to its sequestration in the liver. Moreover, they showed that 753b treatment could effectively reduce the progression of MASLD and development of hepatocellular carcinoma (HCC) in STAM mice even after the mice developed substantial metabolic dysfunction-associated steatohepatitis (MASH or NASH) 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, a disease that is highly prevalent in the Hispanic population in south Texas, especially in our cancer center catchment area. They hope to develop a drug candidate that can be translated into the clinic in the future.
Dr. Zhou is a Professor with Tenure with the Department of Biochemistry and Structural Biology, the Associate Director for Drug Development of the Mays Cancer Center, and the Director of the Center for Innovative Drug Discovery (CIDD).
A BCL-xL/BCL-2 PROTAC effectively clears senescent cells in the liver and reduces MASH-driven hepatocellular carcinoma in mice
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
Nature Aging. 2025 Jan 31. doi: 10.1038/s43587-025-00811-7. Online ahead of print.
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.
Conflict of interest statement
Competing interests: Y.Y., Y.H., P.Z., W.H., G.Z., L.P. and D.Z. are inventors on patents for the use of BCL-xL PROTACs as anti-tumor agents and senolytics. R.H., G.Z. and D.Z. are cofounders of and have equity in Dialectic Therapeutics, which develops BCL-xL/2 PROTACs to treat cancer. The other authors declare no competing interests.