A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms.

Pathological cardiac fibrosis and hypertrophy, key contributors to adverse remodeling that drives heart failure (HF), are not adequately targeted by current therapies. We identified tRNA-Asp-GTC-3'tDR, an ischemia-induced tRNA-derived small RNA (tDR), as an endogenous regulator of both remodeling processes across cardiac fibroblasts and cardiomyocytes. In murine models of myocardial ischemia- and pressure overload-induced HF, cardiac delivery of tRNA-Asp-GTC-3'tDR reduced fibrosis and hypertrophy, preserved cardiac function, and improved survival, with limited three doses conferring durable protection after ischemia, whereas silencing it worsened both. Strikingly, tRNA-Asp-GTC-3'tDR acts through distinct mechanisms in different cell types: in fibroblasts, it assembles stress granules that sequester ribosome-loaded profibrotic transcripts, whereas in cardiomyocytes it engages pseudouridine synthase PUS7 to activate RNA autophagy. Its regulation and functions were confirmed in human cardiac cells and tissues. These findings demonstrate that a single tDR coordinates cell-type-specific protective programs in the heart, suggesting a new therapeutic axis to mitigate HF progression.