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<p>This review synthesizes current evidence on competing endogenous RNA (ceRNA) regulation in acute kidney injury (AKI) and proposes a practical, reproducible framework for computationally guided drug repurposing that aims to rewire pathogenic circRNA–miRNA–mRNA axes. We summarize the ceRNA concept and its biological rationale in renal injury, anchored to foundational descriptions of the ceRNA hypothesis. Building on curated circRNA resources and drug–gene mapping platforms, we present and critically evaluate a five-stage computational framework: (1) multi-omics data mining and ceRNA triplet inference, (2) network pharmacology mapping to drug–gene resources, (3) RNA-aware molecular docking to candidate structured RNA motifs, (4) molecular dynamics (MD) refinement and rescoring, and (5) integrative prioritization with explicit experimental filters for renal safety and tractability. We synthesize methodological best practices and limitations for each stage, with particular attention to the emerging field of RNA-targeted small molecules and their experimental validation. Three illustrative case studies demonstrate how distinct repurposing logics (direct RNA engagement, network/miRNA modulation, pathway-level modulation) can be mapped onto this pipeline and what orthogonal assays are required to progress candidates from in silico nomination to biochemical and in vivo testing. The review concludes with a pragmatic experimental roadmap, clear caveats (RNA structural dynamics, cellular context dependency, miRNA redundancy), and proposals to integrate single-cell and systems-pharmacology approaches to improve replicability and translational potential. By collating the literature and proposing a transparent, stepwise framework with validation benchmarks, this review aims to generate testable, prioritized in-silico hypotheses for RNA-aware repurposing in AKI that require rigorous biochemical and preclinical validation before any consideration of clinical testing. Because AKI arises from multiple, biologically distinct etiologies (for example ischemia–reperfusion injury, sepsis, nephrotoxic injury such as cisplatin exposure, and obstructive causes), candidate drugs and circRNA/miRNA targets must be evaluated in etiology-matched cellular and animal models; the pipeline therefore explicitly recommends etiology-aware filtering and model selection to avoid overgeneralizing findings across all AKI types.</p>

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Therapeutic rewiring of ceRNA networks: a computational pipeline for drug repurposing in acute kidney injury via circRNA–miRNA–mRNA axis disruption

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Ming Wang,
  • Feng Gao

摘要

This review synthesizes current evidence on competing endogenous RNA (ceRNA) regulation in acute kidney injury (AKI) and proposes a practical, reproducible framework for computationally guided drug repurposing that aims to rewire pathogenic circRNA–miRNA–mRNA axes. We summarize the ceRNA concept and its biological rationale in renal injury, anchored to foundational descriptions of the ceRNA hypothesis. Building on curated circRNA resources and drug–gene mapping platforms, we present and critically evaluate a five-stage computational framework: (1) multi-omics data mining and ceRNA triplet inference, (2) network pharmacology mapping to drug–gene resources, (3) RNA-aware molecular docking to candidate structured RNA motifs, (4) molecular dynamics (MD) refinement and rescoring, and (5) integrative prioritization with explicit experimental filters for renal safety and tractability. We synthesize methodological best practices and limitations for each stage, with particular attention to the emerging field of RNA-targeted small molecules and their experimental validation. Three illustrative case studies demonstrate how distinct repurposing logics (direct RNA engagement, network/miRNA modulation, pathway-level modulation) can be mapped onto this pipeline and what orthogonal assays are required to progress candidates from in silico nomination to biochemical and in vivo testing. The review concludes with a pragmatic experimental roadmap, clear caveats (RNA structural dynamics, cellular context dependency, miRNA redundancy), and proposals to integrate single-cell and systems-pharmacology approaches to improve replicability and translational potential. By collating the literature and proposing a transparent, stepwise framework with validation benchmarks, this review aims to generate testable, prioritized in-silico hypotheses for RNA-aware repurposing in AKI that require rigorous biochemical and preclinical validation before any consideration of clinical testing. Because AKI arises from multiple, biologically distinct etiologies (for example ischemia–reperfusion injury, sepsis, nephrotoxic injury such as cisplatin exposure, and obstructive causes), candidate drugs and circRNA/miRNA targets must be evaluated in etiology-matched cellular and animal models; the pipeline therefore explicitly recommends etiology-aware filtering and model selection to avoid overgeneralizing findings across all AKI types.