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Keywords: anti-tumor immunity; carbonic anhydrase IX targeting; metallodrugs; photodynamic therapy; pyroptosis EN anti-tumor immunity carbonic anhydrase IX targeting metallodrugs photodynamic therapy pyroptosis 1 1 1 02/09/22 20220214 NES 220214 B Pyroptose b ist eine einzigartige Form des programmierten Zelltods, die im Wesentlichen proinflammatorisch und entscheidend für die Immunität ist. Anti-tumor immunity, carbonic anhydrase IX targeting, metallodrugs, photodynamic therapy, pyroptosis Innenrücktitelbild: A Carbonic Anhydrase IX (CAIX)-Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti-Tumor Immunity (Angew. [Extracted from the article]

N 6 -methyladenosine (m 6 A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m 6 A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m 6 A modification of suppressor of cytokine signaling 1 ( SOCS1 ) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma ( PPARγ ), CCAAT/enhancer-binding protein alpha ( C/EBPα ), and C/EBPβ . Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N 6 -methyladenosine (m 6 A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsS x -PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O 2 modulator is developed to improve tumor hypoxia. OsS x -PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsS x -PEG NPs elevate RNA m 6 A methylation levels to cause the m 6 A-dependent mRNA degradation of the hypoxia-related genes. Moreover, OsS x -PEG NPs can regulate the expression of RNA m 6 A methyltransferases and demethylases. Finally, DOX@OsS x -PEG (DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m 6 A methylation of hypoxia-related genes in vivo. As the first report about relationship between catalytic nanomaterials and RNA modifications, the research opens a new avenue for unveiling the underlying action mechanisms of hypoxia-modulating nanomaterials and shows potential of regulating RNA modification to overcome chemoresistance., (© 2020 Wiley-VCH GmbH.)