TM4SF1 is a surface marker of senescent pancreatic β-cells

Senescent pancreatic beta (β)-cells accumulate with age and contribute to impaired insulin secretion and progression of type 2 diabetes mellitus (T2DM). Although the urokinase-type plasminogen activator receptor (uPAR; encoded by PLAUR) has been used as a surface marker of senescence in mice and humans, its broad expression across tissues limits therapeutic specificity. Here, we identify transmembrane-4-L-six-family member-1 (TM4SF1) as a selective surface marker of senescent β-cells. Using RNA sequencing, flow cytometry, and immunofluorescence, we demonstrate that TM4SF1 is enriched in p21 (encoded by CDKN1A) senescent β-cells, with minimal expression in non-senescent β-cells or non-pancreatic cell types. TM4SF1⁺ β-cells exhibit reduced insulin content and impaired glucose-stimulated insulin secretion, linking this population to functional decline. Importantly, compared to uPAR, TM4SF1 shows stronger concordance with canonical senescence markers and greater specificity for β-cells. These findings establish TM4SF1 as a robust and selective marker of senescent β-cells and support its potential as a target for β-cell-directed senotherapeutic strategies in T2DM.