<b>Myeloid-specific heparanase aggravates insulitis in type 1 diabetes via heparan sulfate fragments-dependent amplification of macrophage polarization</b>

<jats:p>&lt;p dir="ltr"&gt;The intra-islet heparan sulfate (HS) barrier is essential for β-cell survival, yet its role in type 1 diabetes (T1D) remains incompletely understood. We investigated the expression pattern, pathogenic function, and therapeutic potential of the heparanase-heparan sulfate (HPSE-HS) axis in T1D by integrating single-cell RNA sequencing datasets from human and mouse islets and peripheral immune cells, together with genetic mouse models and pharmacological intervention. HPSE was selectively enriched in myeloid cells, particularly CD14&lt;sup&gt;++&lt;/sup&gt; classical monocytes from patients with T1D and NOD mice, and was associated with activated pro-inflammatory and interferon signaling. In diabetic islets, increased HPSE expression was accompanied by marked degradation of the HS barrier. Myeloid-specific &lt;i&gt;Hpse&lt;/i&gt; deficiency improved glucose tolerance, enhanced insulin secretion, and reduced infiltration of iNOS&lt;sup&gt;+&lt;/sup&gt; macrophages and T cells, whereas islet-specific &lt;i&gt;Hpse&lt;/i&gt; overexpression accelerated autoimmune diabetes and insulitis. Mechanistically, HPSE-mediated HS cleavage generated bioactive fragments that acted as co-stimulatory signals, amplifying IFN-γ-STAT1 signaling and promoting M1 macrophage polarization. Pharmacological inhibition of HPSE with Muparfostat preserved the intra-islet HS barrier and improved glucose homeostasis in non-obese T1D models. Collectively, these findings identify myeloid-derived HPSE as a key driver of T1D pathogenesis through dual effects on HS barrier disruption and inflammatory amplification, and establish the HPSE-HS axis as an important regulator of the islet inflammatory microenvironment and a promising adjuvant therapeutic target for T1D.&lt;/p&gt;</jats:p>