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PROTAC-mediated regulation of programmed cell death: From molecular mechanisms to therapeutic breakthroughs

Hangqi Huang1, Aoli Deng1, Feifan Pan1

  • 1Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.

Innovation (Cambridge (Mass.))
|July 9, 2026
PubMed

Insights

Proteolysis-targeting chimeras (PROTACs) offer a novel way to degrade disease-causing proteins by harnessing the cell's natural disposal system. This technology precisely controls programmed cell death pathways, showing great promise for treating difficult diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Proteolysis-targeting chimeras (PROTACs) are a novel therapeutic modality that induces targeted protein degradation.
  • PROTACs leverage the ubiquitin-proteasome system to selectively eliminate proteins, offering a new approach to drug discovery.
  • Modulating programmed cell death (PCD) pathways is crucial for treating various diseases, but traditional methods face limitations.

Purpose of the Study:

  • To comprehensively review the role of PROTACs in regulating critical programmed cell death (PCD) pathways.
  • To highlight the potential of PROTACs in targeting previously undruggable proteins.
  • To discuss the current clinical progress and future directions of PROTAC technology.

Main Methods:

  • Review of existing literature on PROTACs and their mechanisms of action.
  • Analysis of PROTACs targeting key proteins in ferroptosis, pyroptosis, necroptosis, apoptosis, and autophagy.
  • Examination of clinical trial data and emerging technologies in PROTAC development.

Main Results:

  • PROTACs effectively induce degradation of targets like GPX4, STING, MLKL/RIPK1, BCL-2/MDM2, and others involved in PCD.
  • Over 30 PROTAC candidates are in clinical trials, with notable examples like ARV-471 and KT-474 demonstrating efficacy.
  • Innovative technologies are addressing challenges in delivery, selectivity, and toxicity, expanding PROTAC applications.

Conclusions:

  • PROTACs represent a groundbreaking therapeutic strategy with the potential to overcome drug resistance and treat intractable diseases.
  • Precise control over PCD pathways by PROTACs opens new avenues in precision medicine.
  • Continued research in molecular design, E3 ligase expansion, and combination therapies will further establish PROTACs as transformative solutions.
Keywords:
PROTACsprogrammed cell deathtargeted protein degradationubiquitin-proteasome systemundruggable targets

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