ACE‐mediated Glycosylation Stabilizes PSAP To Promote GPR37‐dependent Macrophage‐Nucleus Pulposus Cells Crosstalk and TGFβ Signaling in Alleviating Intervertebral Disc Degeneration

Abstract Intervertebral disc degeneration (IDD) represents a complex pathological process involving impaired cellular homeostasis and extracellular matrix dysregulation. This study elucidates a previously unrecognized regulatory axis wherein angiotensin‐converting enzyme (ACE) modulates prosaposin (PSAP) stability through coordinated post‐translational modifications. Mechanistically, ACE deficiency enhances O ‐GlcNAc transferase (OGT)‐mediated glycosylation of PSAP at critical serine residues, which in turn suppresses E3 ubiquitin ligase Casitas B‐lineage lymphoma (CBL)‐dependent ubiquitination and proteasomal degradation. The stabilized PSAP protein engages G protein‐coupled receptor 37 (GPR37) on macrophages to promote anti‐inflammatory M2 polarization through ERK/SMAD2/3 signaling cascades, while concomitantly stimulating transforming growth factor‐β (TGFβ) secretion. This paracrine signaling establishes a reciprocal regulatory loop, as secreted TGFβ reinforces PSAP‐Sortilin mediated trafficking in nucleus pulposus cells via PI3K/AKT pathway activation. In vivo therapeutic intervention using engineered PSAP and GPR37 gene‐editing virus‐loaded hydrogels demonstrated significant improvements in disc structural integrity and matrix composition in preclinical IDD models, with these protective effects being dependent on GPR37 receptor activation. The findings reveal the ACE‐PSAP‐GPR37 axis as a fundamental regulatory circuit in disc homeostasis, providing new insights into the molecular pathogenesis of IDD while establishing a conceptual framework for targeted therapeutic development.