Pharmacology of epitranscriptomic modifications: Decoding the therapeutic potential of RNA modifications in drug resistance.

RNA modifications, collectively known as epitranscriptomic modifications, have emerged as critical regulators of gene expression, cellular adaptation, and therapeutic resistance. This review explores the pharmacological potential of targeting RNA modifications, including N6-methyladenosine (m6A) and 5-methylcytosine (m5C), as strategies to overcome drug resistance in cancer. We examine key regulatory enzymes, writers, erasers, and readers-and their roles in modulating RNA stability, translation, and splicing. Advances in combination therapies, integrating RNA modification modulators with conventional chemotherapies and immune checkpoint inhibitors, have shown promising outcomes in reversing multidrug resistance (MDR). Emerging RNA-targeting technologies, such as CRISPR/Cas13 systems and advanced RNA sequencing platforms, further enable precision manipulation of RNA molecules, opening new therapeutic frontiers. However, several challenges persist, including issues related to pharmacokinetics, acquired resistance, and the complexity of epitranscriptomic networks. This review underscores the need for innovative delivery systems, such as lipid nanoparticles and tissue-specific targeting strategies, and highlights the dynamic nature of RNA modifications in response to environmental and therapeutic stress. Ongoing research into non-coding RNA modifications and the interplay between epitranscriptomics and epigenetics offers exciting possibilities for developing novel RNA-targeting therapies. The continued evolution of RNA-based technologies will be crucial in advancing precision medicine, addressing drug resistance, and improving clinical outcomes across multiple diseases.