Proteolysis-targeting chimera (PROTAC): A promising senolytic strategy.
- 2026-03
- Ageing research reviews 115
- Gang Fan
- Qingping Zhang
- Weiming Guo
- Miao Liu
- Dong Tan
- Zhihan Tang
- Jing Yang
- PubMed: 41558613
- DOI: 10.1016/j.arr.2026.103027
Study Design
- Type
- Review
Senescent cells (SCs) accumulate with aging and contribute to the development of age-related pathologies. These cells evade apoptosis through upregulation of senescent cell anti-apoptotic pathways (SCAPs), making their selective elimination, a strategy termed senolysis, a promising therapeutic avenue. Proteolysis-targeting chimeras (PROTACs) represent an emerging class of bifunctional molecules that exploit the ubiquitin-proteasome system to degrade specific target proteins. By concurrently binding to a protein of interest and an E3 ubiquitin ligase, PROTACs catalyze the degradation of SCAP components, offering a novel pharmacological approach to clear SCs. This review summarizes the principles and recent advances in PROTAC technology, with a focus on its application as a senolytic strategy. We highlight how PROTACs can overcome limitations of conventional inhibitors, such as targeting "undruggable" SCAP proteins, and provide a comparative analysis of major PROTAC classes targeting BCL-2 family members, p53, BRD4, SA-β-gal, and other emerging senescence regulators. Furthermore, we also discuss the aging-specific biological and translational challenges, including altered proteasomal activity, pharmacokinetics, tissue microenvironment, and immune clearance, which must be addressed to advance PROTAC senolytics toward clinical use in age-related diseases.