ABSTRACTBackgroundThis study investigates the role of the KEAP1‐NRF2/HO‐1 signaling pathway in inducing ferroptosis and contributing to neuronal damage in schizophrenia.MethodsWe retrieved schizophrenia‐related data and ferroptosis‐related genes from the RNA microarray dataset GSE27383 and FerrDB database, respectively. Bioinformatics data identified KEAP1 as a downregulated gene, which was validated using qRT‐PCR and Western blot. We assessed intracellular Fe2⁺ content, MDA levels, GSH, and GPX4 in the prefrontal cortex and peripheral blood mononuclear cells (PBMCs) of patients with schizophrenia. Cortical interneurons (cINs) were generated from human‐induced pluripotent stem cells (hiPSCs) of patients with schizophrenia and used to explore KEAP1 alterations during neurodevelopment. In addition, KEAP1 overexpression was induced in cINs via transfection with pcDNA KEAP1. The intracellular Fe⁺ levels, oxidative stress indicators, lipid peroxidation, and inflammatory cytokines were measured after transfection. To investigate molecular mechanisms, KI696—a high‐affinity probe that disrupts the KEAP1–NRF2 interaction—was applied, and changes in oxidative stress, lipid peroxidation (C11‐BODIPY staining), iron metabolism, and inflammatory pathways were evaluated.ResultsPatients with schizophrenia exhibited underexpression of KEAP1, a key regulator of ferroptosis, along with elevated intracellular Fe2⁺ levels and increased MDA concentrations, indicating enhanced lipid peroxidation and oxidative stress. Reduced GPX4 activity and GSH levels were also observed, suggesting an increased susceptibility to ferroptosis. To further explore this, cINs derived from hiPSCs of patients with schizophrenia were studied. These cells showed decreased KEAP1 expression. Overexpression of KEAP1 in cINs led to a reduction in intracellular Fe2⁺ concentrations and oxidative damage, highlighting KEAP1's regulatory role in ferroptosis. In addition, treatment with KI696 induced significant alterations in pathways related to oxidative stress, iron metabolism, antioxidant defenses, and inflammation.ConclusionOur findings indicate that the KEAP1‐NRF2/HO‐1 pathway contributes to ferroptosis and neuronal injury in schizophrenia.

21 Jan 2025·Proceedings of the National Academy of Sciences

A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer

Article

Author: Killilea, David W. ; Brady, Donita C. ; Miller, Sophia G. ; Padilla-Benavides, Teresita ; Li, Erin L. ; Messina, Marco S. ; Chang, Christopher J. ; Ralle, Martina ; Ohata, Jun ; Killilea, Alison N. ; Ward, Nathan P. ; Humpel, Hanna I. ; Pezacki, Aidan T. ; Verdejo-Torres, Odette ; Torrente, Laura ; DeNicola, Gina M.

Copper is an essential nutrient for sustaining vital cellular processes spanning respiration, metabolism, and proliferation. However, loss of copper homeostasis, particularly misregulation of loosely bound copper ions which are defined as the labile copper pool, occurs in major diseases such as cancer, where tumor growth and metastasis have a heightened requirement for this metal. To help decipher the role of copper in the etiology of cancer, we report a histochemical activity-based sensing approach that enables systematic, high-throughput profiling of labile copper status across many cell lines in parallel. Coppermycin-1 reacts selectively with Cu(I) to release puromycin, which is then incorporated into nascent peptides during protein translation, thus leaving a permanent and dose-dependent marker for labile copper that can be visualized with standard immunofluorescence assays. We showcase the utility of this platform for screening labile Cu(I) pools across the National Cancer Institute’s 60 (NCI-60) human tumor cell line panel, identifying cell types with elevated basal levels of labile copper. Moreover, we use Coppermycin-1 to show that lung cancer cells with heightened activation of nuclear factor-erythroid 2-related factor 2 (NRF2) possess lower resting labile Cu(I) levels and, as a result, have reduced viability when treated with a copper chelator. This work establishes that methods for labile copper detection can be used to assess cuproplasia, an emerging form of copper-dependent cell growth and proliferation, providing a starting point for broader investigations into the roles of transition metal signaling in biology and medicine.

01 Feb 2023·Redox Biology

Decreased autophagosome biogenesis, reduced NRF2, and enhanced ferroptotic cell death are underlying molecular mechanisms of non-alcoholic fatty liver disease

Article

Author: Liu, Pengfei ; Ooi, Aikseng ; Chen, Jinjing ; Shakya, Aryatara ; Anandhan, Annadurai ; Dodson, Matthew ; White, Eileen ; Garcia, Joe Gn ; Zhang, Donna D ; Chapman, Eli

BACKGROUND AND AIMSCaloric excess and sedentary lifestyles have led to an epidemic of obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). The objective of this study was to investigate the mechanisms underlying high fat diet (HFD)-induced NAFLD, and to explore NRF2 activation as a strategy to alleviate NAFLD.APPROACH AND RESULTSHerein, we demonstrated that high fat diet (HFD) induced lipid peroxidation and ferroptosis, both of which could be alleviated by NRF2 upregulation. Mechanistically, HFD suppressed autophagosome biogenesis through AMPK- and AKT-mediated mTOR activation and decreased ATG7, resulting in KEAP1 stabilization and decreased NRF2 levels in mouse liver. Furthermore, ATG7 is required for HFD-induced NRF2 downregulation, as ATG7 deletion in Cre-inducible ATG7 knockout mice decreased NRF2 levels and enhanced ferroptosis, which was not further exacerbated by HFD. This finding was recapitulated in mouse hepatocytes, which showed a similar phenotype upon treatment with saturated fatty acids (SFAs) but not monounsaturated fatty acids (MUFAs). Finally, NRF2 activation blocked fatty acid (FA)-mediated NRF2 downregulation, lipid peroxidation, and ferroptosis. Importantly, the HFD-induced alterations were also observed in human fatty liver tissue samples.CONCLUSIONSHFD-mediated autophagy inhibition, NRF2 suppression, and ferroptosis promotion are important molecular mechanisms of obesity-driven metabolic diseases. NRF2 activation counteracts HFD-mediated NRF2 suppression and ferroptotic cell death. In addition, SFA vs. MUFA regulation of NRF2 may underlie their harmful vs. beneficial effects. Our study reveals NRF2 as a key player in the development and progression of fatty liver disease and that NRF2 activation could serve as a potential therapeutic strategy.

100 Deals associated with KI-696

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Indication	Highest Phase	Country/Location	Organization	Date
acute stress	Phase 2	United States	Astex Pharmaceuticals, Inc.	-
Pulmonary Disease, Chronic Obstructive	Phase 2	United States	Astex Pharmaceuticals, Inc.	-
acute stress	Preclinical	United States	GSK Plc	-
Pulmonary Disease, Chronic Obstructive	Preclinical	United States	GSK Plc	-

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