Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases.

Ferroptosis is a form of iron-dependent, lipid peroxidation-driven regulatory cell death that has been implicated in the pathogenesis of multiple diseases, including organ injury, ischemia/reperfusion, and neurodegenerative diseases. However, inhibitors that directly and specifically target ferroptosis are not yet available. Here, we identify the compound AS-252424 (AS) as a potent ferroptosis inhibitor through kinase inhibitor library screening. Our results show that AS effectively inhibits lipid peroxidation and ferroptosis in both human and mouse cells. Mechanistically, AS directly binds to the glutamine 464 of ACSL4 to inhibit its enzymatic activity, resulting in the suppression of lipid peroxidation and ferroptosis. By using nanoparticle-based delivery systems, treatment with AS-loaded nanoparticles effectively alleviate ferroptosis-mediated organ injury in mouse models, including kidney ischemia/reperfusion injury and acute liver injury (ALI). Thus, our results identify that AS is a specific and targeted inhibitor of ACSL4 with remarkable antiferroptosis function, providing a potential therapeutic for ferroptosis-related diseases.

Copper(II)-Based Nano-Regulator Correlates Cuproptosis Burst and Sequential Immunogenic Cell Death for Synergistic Cancer Immunotherapy.

Immunogenic cell death (ICD) of tumor cells serves as a crucial initial signal in the activation of anti-tumor immune responses, holding marked promise in the field of tumor immunotherapy. However, low immunogenicity tumors pose challenges in achieving complete induction of ICD, thereby limiting the response rates of immunotherapy in clinical patients. The emergence of cuproptosis as a new form of regulated cell death has presented a promising strategy for enhanced immunotherapy of low immunogenic tumors. To trigger cuproptosis, copper-ionophore elesclomol (ES) had to be employed for the copper-transporting-mediated process. Herein, we proposed a copper(II)-based metal-organic framework nanoplatform (Cu-MOF) to facilitate a cooperative delivery of encapsulated ES and copper (ES-Cu-MOF) to induce cuproptosis burst and enhance ICD of fibrosarcoma. Our results showed that the ES-Cu-MOF nano-regulator could effectively release Cu2+ and ES in response to the intracellular environment, resulting in elevated mitochondrial ROS generation and initiated cuproptosis of tumor cells. Furthermore, sequential ICDs were significantly triggered via the ES-Cu-MOF nano-regulator to activate the anti-tumor immune response. The results of tumor inhibition experiment indicated that the nano-regulator of ES-Cu-MOF obviously accumulated in the tumor site, inducing ICD for dendritic cell activation. This enabled an increased infiltration of cytotoxic CD8+ T cells and consequently enhanced antitumor immune responses for successfully suppressing fibrosarcoma growth. Thus, the copper(II)-based metal-organic framework nano-regulator offered a promising approach for inducing cuproptosis and cuproptosis-stimulated ICD for cancer immunotherapy.