5'tRNA-derived fragments modulate β-cell homeostasis and islet macrophage activation in type 2 diabetes

: Obesity and diabetes impose chronic stress on pancreatic β-cells, while reprogramming of islet-resident macrophages (iMACs) accelerates dysfunction. Here, we identify transfer RNA-derived fragments (tRFs) as previously unrecognized mediators of islet remodeling under metabolic stress. 5'tRFGlu(CTC) and 5'tRFGly(GCC) are elevated in β-cells and iMACs from db/db mice and in islets from individuals with type 2 diabetes; 5'tRFGlu(CTC) also rises in prediabetes and inversely correlates with insulin secretion. Lipotoxicity triggers 5'tRF biogenesis, and targeted inhibition of 5'tRFGlu(CTC) preserves β-cell viability and function under palmitate exposure. In a β-cell/macrophage co-culture model, β-cell contact shapes a distinct iMAC-like phenotype that shifts after palmitate treatment. Inhibiting 5'tRFGlu(CTC) in iMAC-like cells prevents their activation switch and protects β-cells from lipotoxicity. Mechanistically, 5'tRFGlu(CTC) interacts with RNA-binding proteins to control immune activation, extracellular matrix remodeling, and oxidative stress pathways. These findings position tRFs as central effectors of cellular stress responses in both endocrine and immune cells.