ETS1 activates heparanase transcription to drive intra-islet heparan sulfate degradation and macrophage-induced insulitis in type 1 diabetes

-mKO) mice exhibited profound resistance to multiple low-dose streptozotocin (MLD-STZ)-induced T1D insulitis. This protection was driven by the marked suppression of myeloid HPSE expression, which preserved intra-islet HS levels, reduced inflammatory cell infiltration, and enhanced β-cell survival compared with that in wild-type littermates. In conclusion, our findings define a previously unrecognized ETS1-HPSE-HS signaling axis that is involved in macrophage-mediated islet damage in T1D. We demonstrate that ETS1 is a crucial driver of the enzymatic breakdown of the islet basement membrane and the subsequent progression of insulitis, suggesting that targeting the ETS1-mediated transcriptional activation of HPSE offers a novel therapeutic strategy to safeguard the islet microenvironment and slow the progression of T1D.