Proteolysis-targeting Chimeras induce ferroptosis in cancer: From Mechanism to clinical application

Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is a crucial tumor suppression mechanism and promising therapeutic avenue, especially for resistant cancers. However, its clinical translation is hindered by complex regulatory networks, compensatory pathways, and a lack of selective modulators. The advent of Proteolysis-Targeting Chimeras (PROTACs) presents a groundbreaking opportunity to precisely manipulate this pathway. This review systematically explores leveraging PROTAC technology to induce ferroptosis. We first delineate the core regulatory axes, including GPX4, FSP1, and DHODH pathways, and their crosstalk with oncogenic signaling and the tumor microenvironment. The focus then shifts to rational PROTAC design strategies targeting these key nodes, summarizing current preclinical proof-of-concept efforts, primarily against GPX4. Despite this promise, challenges remain, including PROTAC druggability, the dual role of ferroptosis, and compensatory resistance. Future strategies to overcome these hurdles involve developing multi-target degraders, intelligent drug delivery systems, and synergistic combinations with conventional and immunotherapies. The integration of computational tools and AI for accelerated design is also highlighted. In conclusion, PROTAC technology represents a versatile platform for reactivating ferroptosis, holding immense potential to overcome drug resistance and treat refractory cancers. ● PROTACs offer a novel catalytic strategy to induce ferroptosis beyond inhibition. ● Rational design targets undruggable GPX4 and expands the E3 ligase repertoire. ● This approach overcomes cancer-specific therapy resistance via protein degradation. ● Future lies in multi-target degraders and computational/AI-driven design strategies.