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<p>Cytochrome P450 3A5 (CYP3A5) is a critical drug-metabolizing enzyme in human hepatocytes, playing a key role in the metabolism of various clinically relevant drugs, with considerable variability in gene expression across individuals. Long non-coding RNAs (lncRNAs) are likely to be important regulators within the <i>CYP3A5</i> regulatory network in the liver. In this study, we employed a computational approach to estimate Sobol's sensitivity indices (SSI) under generalized linear models, applied to liver RNA expression microarray data (GTEx v8). The SSI-based analysis revealed that the long non-coding RNA LINC02499 exhibits the highest SSI value in relation to <i>CYP3A5</i> expression in the liver. Furthermore, we conducted a comprehensive evaluation of LINC02499's biological characteristics and confirmed its regulatory role in <i>CYP3A5</i> expression through real-time quantitative PCR and Western blotting experiments at the cellular level. We also demonstrated the direct interaction between miR-329-5p and both LINC02499 and <i>CYP3A5</i> mRNA using dual-luciferase reporter assays and electrophoretic mobility shift assays (EMSA). In conclusion, our findings outline a regulatory network in which LINC02499 functions as a molecular sponge, mitigating the post-transcriptional inhibitory effect of miR-329-5p on <i>CYP3A5</i> expression.</p>

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Long non-coding RNA LINC02499 regulates the expression of CYP3A5 in human liver cells

  • 期刊论文

  • 发表日期：

    2025年7月2日

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  • Chengcheng Li,
  • Langzhang Li,
  • Siqi Zhang,
  • Yawen Zhang,
  • Tianxing Yang,
  • Liang Li

摘要

Cytochrome P450 3A5 (CYP3A5) is a critical drug-metabolizing enzyme in human hepatocytes, playing a key role in the metabolism of various clinically relevant drugs, with considerable variability in gene expression across individuals. Long non-coding RNAs (lncRNAs) are likely to be important regulators within the CYP3A5 regulatory network in the liver. In this study, we employed a computational approach to estimate Sobol's sensitivity indices (SSI) under generalized linear models, applied to liver RNA expression microarray data (GTEx v8). The SSI-based analysis revealed that the long non-coding RNA LINC02499 exhibits the highest SSI value in relation to CYP3A5 expression in the liver. Furthermore, we conducted a comprehensive evaluation of LINC02499's biological characteristics and confirmed its regulatory role in CYP3A5 expression through real-time quantitative PCR and Western blotting experiments at the cellular level. We also demonstrated the direct interaction between miR-329-5p and both LINC02499 and CYP3A5 mRNA using dual-luciferase reporter assays and electrophoretic mobility shift assays (EMSA). In conclusion, our findings outline a regulatory network in which LINC02499 functions as a molecular sponge, mitigating the post-transcriptional inhibitory effect of miR-329-5p on CYP3A5 expression.