Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by an Autophagy Promotor

Abstract

Until now, ferroptotic therapeutic strategies remain simple, although ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on MnO2@HMCu2–x S nanocomposites (HMCMs) for efficient tumor ablation. The HMCMs possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by a Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxide (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated that the HMCM exhibited superior anticancer effect in human breast cancer models and that the combined therapeutic system afforded the next generation of ferroptotic therapy for combatting malignant tumors.

RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

“…Ferroptosis is a type of iron‐dependent oxidative cell death (Tang et al, 2019), and is characterized by high intracellular Fe 2+ levels and low GSH levels. It is always accompanied by oxidative stress (An et al, 2019; Sui et al, 2018; Wang, Chen, Shi, Jiao, & Gong, 2019). However, it is unclear whether RB could induce ferroptotic cell death in CRC cells.…”

Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload

“…Intracellular ROS can be reduced to their corresponding alcohols or water by GPX4-catalyzed GSH. The cystine/glutamate transporter (xCT, also known as SLC7A11) is an important transport carrier of cystine used in GSH synthesis 65,66 . The JNK/cellular tumor antigen p53 is the primary signal effector regulating xCT in oxidative stress.…”

GSH‐Depleted Nanozymes with Hyperthermia‐Enhanced Dual Enzyme‐Mimic Activities for Tumor Nanocatalytic Therapy

“…[ 15 ] Additionally, a MnO 2 @HMCu 2–x S nanocomposite with photothermal‐enhanced GSH depletion capability, has been constructed to induce ferroptosis for efficient tumor ablation. [ 16 ] Thus, the photothermal performance and hyperthermia‐enhanced catalytic activity of nanozymes are expected to achieve a synergistic effect of PTT and tumor nanocatalytic therapy.…”