FTO in cardiovascular diseases: mechanisms, context dependence, and translational opportunities.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Their regulation involves not only classical genetic mechanisms but also dynamic epitranscriptomic control. The fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) RNA demethylase, has been implicated in cardiovascular disease. Evidence shows that the role of FTO in CVDs is strongly context dependent, with both protective and harmful effects reported in different settings. This review summarizes the genetic, molecular, and epitranscriptomic features of FTO and presents a framework in which FTO acts through three connected axes: metabolic remodeling, immuno-inflammatory signaling, and electrophysiological and structural remodeling. By regulating key transcripts through RNA methylation-related post-transcriptional control, FTO may modulate cellular responses to hypoxia, inflammation, and metabolic stress. It also reviews the context-specific roles of FTO in atherosclerosis, hypertension, myocardial infarction, ischemia-reperfusion injury, myocardial fibrosis, heart failure, arrhythmia and myocarditis. These different effects seem to depend on cell type, target selection, and disease stage, which suggests that FTO acts as a context-sensitive epitranscriptomic switch rather than a simple one-way effector. FTO represents a promising but complex therapeutic target. Pharmacological inhibition of FTO has shown benefit in some disease settings, but other studies suggest that selective activation or context-dependent modulation may also be needed. However, the precise biochemical functions of FTO and the relative contributions of RNA modifications remain incompletely understood. Key barriers include limited causal evidence, poor cell-specific resolution, and incomplete integration with other epigenetic layers.