Yang Yang, Jn-Simon Natacha, He Yonghan, Sun Chunbao, Zhang Peiyi, Hu Wanyi, Tian Tian, Zeng Huadong, Basha Sreenivasulu, Huerta Araceli S, Sun Lu-Zhe, Yin Xian-Ming, Hromas Robert, Zheng Guangrong, Pi Liya, Zhou Daohong
Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA.
Nat Aging. 2025 Mar;5(3):386-400. doi: 10.1038/s43587-025-00811-7. Epub 2025 Jan 31.
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.
衰老细胞（SnCs）的积累在许多与年龄相关的疾病中起致病作用，并且也与代谢功能障碍相关脂肪性肝病（MASLD）的发病机制和进展有关。能够选择性杀死SnCs的衰老细胞溶解剂有潜力被开发为这些疾病的治疗药物。在此我们报告一项发现，即一种双BCL-xL/BCL-2蛋白酶靶向嵌合体（PROTAC）753b，作为一种强效且具有肝脏靶向性的衰老细胞溶解剂发挥作用。我们发现，用753b治疗可选择性减少老年小鼠和STAM小鼠肝脏中的SnCs，部分原因是它在肝脏中被隔离。此外，即使在小鼠出现严重的代谢功能障碍相关脂肪性肝炎（MASH）和肝纤维化后，753b治疗仍可有效减轻STAM小鼠中MASLD的进展和肝细胞癌（HCC）的发展。这些发现表明，BCL-xL/BCL-2 PROTAC有潜力被开发为治疗MASLD的药物，以减少MASH驱动的HCC。
