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While chronic, unresolved endoplasmic reticulum (ER) stress is known to compromise PDLSC stemness, the precise underlying mechanisms remain elusive. Recent studies identify glutamine\u2010rich protein 1 (QRICH1) as a crucial regulator governing cell entry into terminal or adaptive unfolded protein response (UPR). Herein, analysis of single\u2010cell transcriptomic datasets reveals that QRICH1 modulates fibroblast and osteoblast functions. QRICH1 is markedly elevated in human diabetic periodontal tissues and damaged PDLSCs, with its expression regulated by UPR. Transcriptomic profiling indicates enrichment in protein oligomerization, calcium homeostasis, and NF\u2010\u03baB signaling in PDLSCs under high\u2010glucose and inflammatory conditions. Functional assays demonstrate that QRICH1 drives PDLSC dysfunction by sustaining global protein synthesis, amplifying NF\u2010\u03baB activation through interaction with p65, and enhancing UPR\u2010mediated apoptosis. Moreover, transcriptomic analysis following QRICH1 depletion confirms the downregulation of biosynthetic and stress\u2010response pathways, corroborating its role in regulating protein homeostasis. In addition, QRICH1 knockdown effectively restores cellular function in vitro. Adeno\u2010associated virus (AAV)\u2010mediated\n                    <jats:italic>Qrich1<\/jats:italic>\n                    knockdown mitigates alveolar bone loss while suppressing ER stress and NF\u2010\u03baB activation. Collectively, these findings reveal that QRICH1 drives PDLSC dysfunction by enhancing NF\u2010\u03baB signaling and UPR\u2010mediated apoptosis, highlighting its therapeutic potential in diabetic periodontitis.\n                  <\/jats:p>","DOI":"10.1002\/advs.76650","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:45:25Z","timestamp":1784547925000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["QRICH1 Disrupts Endoplasmic Reticulum Homeostasis and Amplifies NF\u2010\u03baB Signaling in Periodontal Ligament Stem Cells to Exacerbate Diabetic Periodontitis"],"prefix":"10.1002","volume":"13","author":[{"given":"Han","family":"Li","sequence":"first","affiliation":[{"name":"College of Stomatology Chongqing Medical University  Chongqing People's Republic of China"},{"name":"Chongqing Key Laboratory For Oral Diseases  Chongqing People's Republic of China"},{"name":"Chongqing 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