Small-Molecule Ferritin Degrader as a Pyroptosis Inducer

Abstract

Exploring the response of malignant cells to intracellular metabolic stress is critical for understanding pathologic processes and developing anticancer therapies. Herein, we developed ferritin-targeting proteolysis targeting chimeras (PROTACs) to establish the iron excess stress inside cancer cells and investigated subsequent cellular behaviors. We conjugated oleic acid that binds to the ferritin dimer to the ligand of von Hippel–Lindau (VHL) E3 ligase through an alkyl linker. The screened chimera, DeFer-2, degraded ferritin and then rapidly elevated the free iron content, thereby initiating the caspase 3-GSDME-mediated pyroptosis in cancer cells rather than typical ferroptosis that is always associated with iron ion overload. According to its structural and physicochemical characteristics, DeFer-2 was loaded into a tailored albumin-based nano-formulation, which substantially inhibited tumor growth and prolonged the survival time of mice bearing B16F10 subcutaneous tumors with negligible adverse effects. This study developed a ferritin-targeting PROTAC for iron overload stress, revealed iron metabolic dysregulation-mediated pyroptosis, and provided a PROTAC-based pyroptosis inducer for anticancer treatment.

Nano-PROTACs: state of the art and perspectives

“…Considering this, Chen et al 78 conjugated oleic acid to the ligand of E3 ligase through different alkyl linkers to screen the most effective chimera (Fig. 7B).…”

Modulation of Metal Homeostasis for Cancer Therapy

“…Chen et al . demonstrated that the production of ROS mediated by iron excess stress activated caspase‐3/gasdermin E (GSDME)‐mediated pyroptosis [35b] . Therefore, the mechanisms of iron overload‐mediated programmed cell death (PCD) are complex.…”

A dynamic cascade DNA nanocomplex to synergistically disrupt the pyroptosis checkpoint and relieve tumor hypoxia for efficient pyroptosis cancer therapy

“…Via attacking ROS on the subcellular membrane, pyroptosis-inducing factors were released for the subsequent pyroptosis of tumor cells. [42][43][44][45] Pyroptosis could be employed via the NLRP3-caspase 1-GSDMD pathway, including the formation of NLRP3 inammasomes to active caspase-1. Thereaer, both pro-inammatory cytokines IL-1b (Pro-1L-1b) and gasdermin D (GSDMD) were cleaved to release the N-terminal domain (GSDMD-N) and 1L-1b for executing pyroptosis via the pore-forming activities.…”