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This study elucidates a previously unrecognized regulatory axis wherein angiotensin\u2010converting enzyme (ACE) modulates prosaposin (PSAP) stability through coordinated post\u2010translational modifications. Mechanistically, ACE deficiency enhances\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAc transferase (OGT)\u2010mediated glycosylation of PSAP at critical serine residues, which in turn suppresses E3 ubiquitin ligase Casitas B\u2010lineage lymphoma (CBL)\u2010dependent ubiquitination and proteasomal degradation. The stabilized PSAP protein engages G protein\u2010coupled receptor 37 (GPR37) on macrophages to promote anti\u2010inflammatory M2 polarization through ERK\/SMAD2\/3 signaling cascades, while concomitantly stimulating transforming growth factor\u2010\u03b2 (TGF\u03b2) secretion. This paracrine signaling establishes a reciprocal regulatory loop, as secreted TGF\u03b2 reinforces PSAP\u2010Sortilin mediated trafficking in nucleus pulposus cells via PI3K\/AKT pathway activation. In vivo therapeutic intervention using engineered PSAP and GPR37 gene\u2010editing virus\u2010loaded 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\u2010PSAP\u2010GPR37 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.\n                  <\/jats:p>","DOI":"10.1002\/advs.202510662","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T12:35:54Z","timestamp":1760445354000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ACE\u2010mediated Glycosylation Stabilizes PSAP To Promote GPR37\u2010dependent Macrophage\u2010Nucleus Pulposus Cells Crosstalk and TGF\u03b2 Signaling in Alleviating Intervertebral Disc Degeneration"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8666-1974","authenticated-orcid":false,"given":"Youfeng","family":"Guo","sequence":"first","affiliation":[{"name":"Department of spine surgery Shanghai 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