Circular RNA Regulation of Human Drug-Metabolism Genes: Mechanisms and Clinical Implications

Abstract

Circular RNAs (circRNAs) have emerged as critical post-transcriptional regulators in diverse biological processes, including the modulation of drug-metabolism genes. Recent research highlights the pivotal roles circRNAs play in influencing pharmacokinetics, pharmacodynamics, and interindividual variability in drug response. This review synthesizes current evidence on circRNA regulation of human drug-metabolism genes, explores underlying mechanisms, and discusses the clinical and therapeutic implications for precision medicine. We present up-to-date findings, focusing on clinical relevance, risk stratification, diagnostic avenues, and novel treatment strategies, with an emphasis on recent advances and guideline-based recommendations for healthcare professionals.

Introduction

The human body’s ability to metabolize drugs is crucial for therapeutic efficacy and safety. Drug-metabolism genes, primarily belonging to the cytochrome P450 (CYP) superfamily, phase II conjugation enzymes, and transporters, govern the pharmacokinetics of administered agents. While genetic polymorphisms contribute significantly to variability in drug metabolism, emerging evidence underscores the regulatory influence of non-coding RNAs, including circRNAs. CircRNAs, characterized by their covalently closed-loop structure, exhibit remarkable stability and act as microRNA sponges, RNA-binding protein modulators, and even regulators of gene expression. Their involvement in the fine-tuning of drug-metabolizing enzymes is increasingly recognized, offering new perspectives for clinical pharmacology and precision medicine.

Epidemiology / Disease Burden

Adverse drug reactions (ADRs) and suboptimal drug efficacy remain significant challenges globally, contributing to morbidity, hospitalizations, and healthcare costs. Interindividual variability in drug metabolism is a major determinant of these outcomes. The prevalence of CYP polymorphisms, such as CYP2D6 or CYP2C19, varies across populations, influencing the frequency of poor, intermediate, and ultra-rapid metabolizers. However, genomic data alone do not account for all observed variability, suggesting additional layers of regulation. Recent transcriptomic studies reveal differential circRNA expression in hepatic tissue and peripheral blood, correlating with altered metabolism phenotypes and highlighting the potential epidemiological impact of circRNA-mediated regulation.

Pathophysiology

CircRNAs exert their regulatory functions through multiple mechanisms. Primarily, they act as competitive endogenous RNAs (ceRNAs) by sponging microRNAs (miRNAs) that target drug-metabolism mRNAs, thus modulating gene expression. For example, circRNA_0023642 has been shown to sequester miR-490-3p, leading to upregulation of CYP2C9. CircRNAs also interact with RNA-binding proteins, influencing the stability or translation of mRNAs encoding drug-metabolizing enzymes. Furthermore, circRNAs may participate in epigenetic modulation, impacting chromatin remodeling and transcriptional activity of drug-metabolism genes. Dysregulation of these processes can alter enzymatic activity, affecting drug clearance and toxicity risk.

Risk Factors

Risk factors for altered circRNA-mediated regulation of drug-metabolism genes include genetic variants in circRNA loci, environmental exposures (such as xenobiotics or diet), age, sex, comorbidities (notably liver diseases), and concurrent medications. Hepatic inflammation or oxidative stress can modify circRNA expression profiles, further influencing enzyme activities. Polymorphisms in miRNA binding sites or RNA-binding proteins may also modulate circRNA function, contributing to interindividual and interethnic differences in drug response.

Clinical Features

Clinically, dysregulation of circRNAs involved in drug metabolism may manifest as unexpected drug toxicity, therapeutic failure, or exaggerated pharmacological effects. For instance, impaired circRNA-mediated suppression of CYP3A4 could lead to subtherapeutic drug levels for substrates of this enzyme, while overexpression might precipitate adverse reactions due to drug accumulation. These features are often nonspecific and may overlap with those associated with genetic polymorphisms, underscoring the need for integrative diagnostic approaches.

Diagnosis

Current diagnostic evaluation of drug metabolism relies on genotyping of key pharmacogenes and phenotyping via probe drugs. However, incorporating circRNA profiling—using quantitative PCR, RNA sequencing, or circRNA microarrays—offers additional predictive power. Circulating circRNAs serve as minimally invasive biomarkers, reflecting hepatic enzyme activity and providing dynamic information that complements static genetic data. Integrating circRNA signatures with clinical pharmacogenomics could enhance risk stratification for ADRs and guide individualized therapy.

Treatment & Management

Management strategies for patients with aberrant drug metabolism traditionally involve dose adjustment, therapeutic drug monitoring, or switching to alternative agents. With growing knowledge of circRNA-mediated regulation, targeted interventions are being explored. RNA-based therapeutics, such as antisense oligonucleotides or circRNA mimics/inhibitors, hold promise in modulating the expression of specific drug-metabolizing enzymes. Personalized therapy could be optimized by considering both genetic and epigenetic (circRNA) determinants of metabolism, reducing the risk of ADRs and improving therapeutic outcomes.

Recent Advances / Emerging Therapies

Recent advances include the identification of specific circRNAs that directly influence the expression of major drug-metabolizing enzymes. For example, studies have elucidated the role of circHIPK3 in regulating CYP2E1 and circCYP24A1 in the metabolism of vitamin D analogs. The application of high-throughput sequencing and bioinformatics has expanded the circRNA catalog, facilitating the discovery of novel regulatory axes. Preclinical models demonstrate the feasibility of targeting circRNAs to modulate drug-metabolizing capacity, with implications for overcoming drug resistance in oncology and optimizing pharmacotherapy in polypharmacy settings.

Guideline Recommendations

While clinical guidelines currently emphasize pharmacogenetic testing, leading bodies such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the PharmGKB consortium acknowledge the emerging importance of epigenetic factors. It is anticipated that future updates will incorporate circRNA profiling as a complementary tool for precision dosing and risk assessment. Clinicians are encouraged to remain abreast of ongoing research and to consider participation in clinical trials evaluating circRNA-informed therapeutic strategies.

Conclusion

CircRNAs represent a novel and clinically significant layer of regulation in human drug metabolism. Their influence extends beyond static genomic variation, dynamically modulating the expression and activity of key drug-metabolizing enzymes. Incorporating circRNA profiling into clinical practice has the potential to transform personalized medicine, optimizing efficacy and minimizing adverse outcomes. Continued research is warranted to translate these insights into robust diagnostics and targeted interventions for improved patient care.