Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

Ferroptosis inhibitors: past, present and future

Gallium ion (Ga3+) has long been believed to disrupt ferric homeostasis in the body by competing with iron cofactors in metalloproteins, ultimately leading to cell death. This study revealed that through an indirect pathway, gallium can trigger ferroptosis, a type of non-apoptotic cell death regulated by iron. This is exemplified by the gallium complex of the salen ligand (Ga-1); we found that Ga-1 acts as an effective anion transporter that can affect the pH gradient and change membrane permeability, leading to mitochondrial dysfunction and the release of ferrous iron from the electron transfer chain (ETC). In addition, Ga-1 also targeted protein disulfide isomerases (PDIs) located in the endoplasmic reticulum (ER) membrane, preventing the repair of the antioxidant glutathione (GSH) system and thus enforcing ferroptosis. Finally, a combination treatment of Ga-1 and dietary polyunsaturated fatty acids (PUFAs), which enhances lipid peroxidation during ferroptosis, showed a synergistic effect both in vitro and in vivo. This study provided us with a strategy to synergistically induce Ferroptosis in tumor cells, thereby enhancing the anti-neoplastic effect.

Gallium Triggers Ferroptosis through a Synergistic Mechanism.

Chemotherapeutic drug-induced acute kidney injury (AKI) involves pathologically increased labile iron species in the kidneys that mediate the excessive generation of reactive oxygen species (ROS) to induce ferroptosis and apoptosis, subsequently driving renal dysfunction. Herein, we report renal clearable quantum dot-drug conjugates (QDCs) composed of carbon quantum dot (CDs), deferoxamine (DFO), and poly(ethylene glycol) (PEG) for attenuating chemotherapeutic drug-induced AKI. The CDs component in QDCs can not only provide DFO with high renal specificity to effectively remove the pathological labile iron species in the kidneys to block the source of ROS generation but also exert high antioxidative effects to avoid renal oxidative damage caused by the ROS that have been overproduced. In cisplatin-induced AKI mice, QDCs can inhibit ferroptosis and apoptosis with high efficacy for AKI treatment. This study will provide a new paradigm to realize enhanced therapeutic efficacy for AKI by simultaneously removing the pathological labile iron species and eliminating overproduced ROS in the kidneys to achieve the goal of addressing both symptoms and root causes.

Renal Clearable Quantum Dot-Drug Conjugates Modulate Labile Iron Species and Scavenge Free Radicals for Attenuating Chemotherapeutic Drug-Induced Acute Kidney Injury.

Cellular redox homeostasis is highly dependent on endogenous antioxidant systems, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The nanozymes mimicking the catalytic activities of natural antioxidant systems serve as potential candidates for the therapy of reactive oxygen species (ROS)-related diseases. However, previously reported metal-containing nanozymes possessed unsatisfactory catalytic activity and inevitable peroxidase activity, limiting their translational applications. Therefore, inspired by the superior ROS scavenging activities of natural polyphenols and metal-free carbon dots (CDs) with ultra-small size, phenol-functionalized CDs that mimic endogenous antioxidant system have been fabricated. The SOD activity was determined at an extremely high level (18187 U/mg), which was substantially comparable to natural SOD. Notably, this study reveals for the first time that CDs, as selenium-free nanomaterials, show robust GPx activity in vitro. The theory calculation suggests that the bond dissociation of phenols on CDs is considerably lower than selenocysteine of natural GPx, which facilitates the formation of peroxide intermediate to initiate GPx-like reactions. Furthermore, the kidney-targeting and intracellular antioxidant mimicking properties contribute to the effective alleviating cisplatin-induced acute kidney injury via suppressing oxidative stress-mediated ferroptosis in vivo. These results provide an effective polyphenol-functionalized strategy for synthesizing metal-free multifunctional antioxidant nanozyme to treat ROS-related diseases. 

Metal-free multifunctional nanozymes mimicking endogenous antioxidant system for acute kidney injury alleviation

Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is a serious kidney disease with high morbidity and mortality. However, there is no effective clinical treatment strategy. Herein, we developed a CD44 targeting nanoplatform based on HA-assembled melanin NPs covalently coupled with dexamethasone for I/R-induced AKI therapy by alleviating oxidative/inflammatory- induced damage. The constructed HA-MNP-DXM NPs had good dispersion, stability, and broad-spectrum scavenging capabilities against multiple reactive free radicals. Moreover, the NPs could be efficiently internalized and exhibited antioxidative, anti-inflammatory, and antiapoptotic effects in CoCl2-stimulated renal tubular epithelial NRK-52E cells. Furthermore, the I/R-induced AKI murine model was established to evaluate the in vivo performance of NPs. The results suggested the NPs could specifically target impaired kidneys upon intravenous administration according to NIR-II fluorescence imaging and showed high biosafety. Importantly, the NPs could improve renal function, alleviate oxidative stress and inflammatory reactions, inhibit apoptosis of tubular cells, and restore mitochondrial structure and function, exhibiting excellent therapeutic effects. Further therapeutic mechanism indicated the NPs maintained the cellular/mitochondrial redox balance by modulating the Nrf2 and HO-1 expression. Therefore, the NPs can be a promising therapeutic candidate for the treatment of I/R-induced AKI. 

CD44-targeted melanin-based nanoplatform for alleviation of ischemia/reperfusion-induced acute kidney injury.

Targeting iron metabolism using gallium nanoparticles to suppress ferroptosis and effectively mitigate acute kidney injury

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Targeting iron metabolism using gallium nanoparticles to suppress ferroptosis and effectively mitigate acute kidney injury