Publications
8 June 2026
5’tRNA-derived fragments modulate β-cell homeostasis and islet macrophage activation in type 2 diabetes
Abstract
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.