Non-Coding RNAs in Cancer: Decoding Regulatory Networks for Liquid Biopsy Applications

Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and cellular homeostasis, and their dysregulation is now recognized as a hallmark of cancer. Over the past decades, extensive research has demonstrated that diverse ncRNA classes, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other small ncRNA species, participate in complex regulatory networks that influence tumor initiation, progression, metastasis, and therapy response. Through mechanisms such as transcriptional regulation, post-transcriptional gene silencing, epigenetic modulation, and competitive endogenous RNA interactions, ncRNAs shape the molecular circuitry underlying cancer development. In addition to their functional roles in tumor biology, many ncRNAs are released into biological fluids and can be detected as circulating molecules in blood, urine, saliva, and other biofluids. Their remarkable stability in extracellular environments has generated considerable interest in their use as minimally invasive biomarkers in liquid biopsy applications. Emerging evidence has shown that circulating ncRNAs (c-ncRNAs) can support cancer detection, disease stratification, and treatment monitoring. This narrative review provides an integrated view that links ncRNA-mediated regulatory networks with their application as liquid biopsy biomarkers, positioning ncRNAs as comprehensive indicators of tumor conditions. Particular emphasis is placed on c-ncRNA biomarkers, the integration of multiple ncRNA classes, and multi-analyte biomarker strategies that combine ncRNAs with complementary circulating molecules such as cell-free DNA and protein markers. Finally, we discuss the technical and clinical challenges that currently limit the translation of ncRNA-based diagnostics into clinical practice and highlight future directions for advancing ncRNA-guided liquid biopsy approaches in precision oncology.