The Clinical Relevance of FTO as a Demethylase Beyond Cancer: Molecular Mechanisms and Therapeutic Opportunities

The fat mass and obesity-associated (FTO) gene is a key gene that has been linked to obesity and metabolic regulation. FTO single nucleotide polymorphisms (SNPs) significantly contribute to the pathophysiology of various multisystem diseases via epigenetic mechanisms. Although FTO has been extensively reviewed in the context of cancer, a comprehensive evaluation of its role in non-malignant diseases is currently lacking. This review aimed to systematically assess the molecular functions of FTO in the context of diseases other than cancer based on recent insights from the literature. Relevant studies were retrieved by systematically searching the PubMed database to explore the mechanisms through which FTO acts as a mediator of demethylation, its biological activities, and its functional roles in a spectrum of non-oncologic diseases. To explore pharmacological interactions, AutoDockTools 1.5.7 was used to simulate binding interactions between FTO and conventional therapeutic agents. Additionally, we conducted a bibliometric analysis using VOSviewer to visualize the frequency and co-occurrence of FTO-related terms, thereby helping to map research trends and knowledge gaps in the field. FTO regulates gene expression by modulating RNA methylation, particularly through the demethylation of N6-methyladenosine (m⁶A), thereby influencing RNA splicing, stability, and translation. This regulatory activity plays a major role in processes such as inflammation and fibrosis. Dysregulation of FTO has been implicated in several non-malignant diseases, including metabolic disorders, neurological diseases, and cardiovascular conditions. Computational docking studies showed that FTO exhibited strong binding affinity with two drugs and moderate affinity with eight others. Bibliometric analysis revealed high-frequency keywords and visualized research hotspots pertaining to FTO, providing valuable insight into current areas of scientific interest and potential future directions of study. FTO functions as a key epigenetic regulator in non-cancerous diseases and represents a promising biomarker and therapeutic target. Our findings underscore the importance of FTO-drug interactions and suggest that small-molecule FTO modulators may hold therapeutic value for managing a variety of non-oncologic conditions.