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<p>The renal cancer stem cells (RCSCs) have highly proliferation, resistance to radiotherapy and chemotherapy, and enhanced invasive and tumorigenic capacities characteristics. 3-Aroyl-1,4-diarylpyrrole (ARDAP) is a potent microtubule inhibitor developed by our team; however, its specific killing effects on RCSCs remain unknown. Furthermore, clinical application of ARDAP is restricted by shortcomings such as poor water solubility and low utilization rates. Here, we developed polyethylenimine-coated superparamagnetic iron oxide nanoparticles loaded with ARDAP (ARDAP@SPION-PEI) to overcome these barriers and evaluated their efficacy in mouse RCSCs (mRCSCs) and zebrafish. In vitro and in vivo experiments demonstrated that ARDAP@SPION-PEI significantly inhibited mRCSCs proliferation, migration, and tumorigenicity while suppressing angiogenesis in zebrafish. ARDAP@SPION-PEI treatment significantly upregulated the expression of key PANoptosis pathway genes. Assay for transposase-accessible chromatin using sequencing revealed widespread chromatin accessibility alterations, with prominent enrichment of the transcription factor zinc finger protein 148 (ZFP148). Luciferase reporter assays demonstrated that ZFP148 directly bound to and activated promoters of key PANoptosis-related genes, including receptor-interacting serine/threonine kinase 3 (<i>Ripk3</i>), gasdermin D (<i>Gsdmd</i>), IL-1β (<i>Il1b</i>), and caspase-1 (<i>Casp1</i>). Chromatin immunoprecipitation–polymerase chain reaction further showed significantly enhanced promoter occupancy at the histone H3 lysine 4 trimethylation site following treatment, indicating transcriptionally active chromatin states. Silencing <i>ZFP148</i> attenuated gene activation and reduced cell death induction. In conclusion, ARDAP@SPION-PEI induces mRCSC PANoptosis by remodeling chromatin structure to promote ZNF148-mediated transcription, offering a promising epigenetic-based nanotherapeutic strategy for renal cancer.</p>

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Superparamagnetic iron oxide nanoparticle-driven 3-aroyl-1,4-diarylpyrrole nanocomposites (ARDAP@SPION-PEI) mediate renal cancer cell PANoptosis by regulating chromatin accessibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月15日

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  • Hongliang Shen,
  • Zeyu Cui,
  • Yilun Wu,
  • Michela Puxeddu,
  • Yanchen Lai,
  • Ren Mo,
  • Boyu Yang,
  • Yinong Niu,
  • Yichao Wen,
  • Xiling Du,
  • Romano Silvestri,
  • Te Liu

摘要

The renal cancer stem cells (RCSCs) have highly proliferation, resistance to radiotherapy and chemotherapy, and enhanced invasive and tumorigenic capacities characteristics. 3-Aroyl-1,4-diarylpyrrole (ARDAP) is a potent microtubule inhibitor developed by our team; however, its specific killing effects on RCSCs remain unknown. Furthermore, clinical application of ARDAP is restricted by shortcomings such as poor water solubility and low utilization rates. Here, we developed polyethylenimine-coated superparamagnetic iron oxide nanoparticles loaded with ARDAP (ARDAP@SPION-PEI) to overcome these barriers and evaluated their efficacy in mouse RCSCs (mRCSCs) and zebrafish. In vitro and in vivo experiments demonstrated that ARDAP@SPION-PEI significantly inhibited mRCSCs proliferation, migration, and tumorigenicity while suppressing angiogenesis in zebrafish. ARDAP@SPION-PEI treatment significantly upregulated the expression of key PANoptosis pathway genes. Assay for transposase-accessible chromatin using sequencing revealed widespread chromatin accessibility alterations, with prominent enrichment of the transcription factor zinc finger protein 148 (ZFP148). Luciferase reporter assays demonstrated that ZFP148 directly bound to and activated promoters of key PANoptosis-related genes, including receptor-interacting serine/threonine kinase 3 (Ripk3), gasdermin D (Gsdmd), IL-1β (Il1b), and caspase-1 (Casp1). Chromatin immunoprecipitation–polymerase chain reaction further showed significantly enhanced promoter occupancy at the histone H3 lysine 4 trimethylation site following treatment, indicating transcriptionally active chromatin states. Silencing ZFP148 attenuated gene activation and reduced cell death induction. In conclusion, ARDAP@SPION-PEI induces mRCSC PANoptosis by remodeling chromatin structure to promote ZNF148-mediated transcription, offering a promising epigenetic-based nanotherapeutic strategy for renal cancer.