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

Proteolysis-targeting chimeras (PROTACs) represent a revolutionary therapeutic strategy that achieves selective protein degradation through the ubiquitin-proteasome system, offering transformative potential for modulating programmed cell death (PCD) pathways. This review comprehensively examines the central role of PROTACs in regulating critical PCD mechanisms, including ferroptosis induction via GPX4 degradation, pyroptosis regulation through stimulator of interferon genes (STING) targeting, necroptosis modulation by MLKL/RIPK1 degradation, apoptosis activation through BCL-2/MDM2 elimination, and autophagy regulation via dual ubiquitin-proteasome and lysosomal pathways. These approaches effectively address the limitations of traditionally "undruggable" targets while demonstrating unique mechanistic properties and clinical promise. Currently, over 30 PROTAC candidates have entered clinical trials, including the estrogen receptor (ER) degrader ARV-471 for breast cancer and the IRAK4 degrader KT-474 for inflammatory diseases, both showing remarkable efficacy in overcoming drug resistance. While challenges remain in delivery systems, E3 ligase selectivity, and toxicity management, innovative technologies, such as nanocarriers, covalent PROTACs, and novel E3 ligases (e.g., RNF114) are advancing PROTAC applications in oncology, neurodegenerative disorders, and immune-related diseases. Future research will focus on optimizing molecular design, expanding the E3 ligase repertoire, and developing combination therapies. These efforts will establish PROTACs as groundbreaking solutions for intractable diseases, with their precise control of PCD pathways opening new therapeutic avenues. The technology's ability to selectively modulate cell death mechanisms positions it as a transformative approach in precision medicine.