QRICH1 Disrupts Endoplasmic Reticulum Homeostasis and Amplifies NF-κB Signaling in Periodontal Ligament Stem Cells to Exacerbate Diabetic Periodontitis.

Functional impairment of periodontal ligament stem cells (PDLSCs) drives tissue destruction in diabetic periodontitis. While chronic, unresolved endoplasmic reticulum (ER) stress is known to compromise PDLSC stemness, the precise underlying mechanisms remain elusive. Recent studies identify glutamine-rich protein 1 (QRICH1) as a crucial regulator governing cell entry into terminal or adaptive unfolded protein response (UPR). Herein, analysis of single-cell 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-κB signaling in PDLSCs under high-glucose and inflammatory conditions. Functional assays demonstrate that QRICH1 drives PDLSC dysfunction by sustaining global protein synthesis, amplifying NF-κB activation through interaction with p65, and enhancing UPR-mediated apoptosis. Moreover, transcriptomic analysis following QRICH1 depletion confirms the downregulation of biosynthetic and stress-response pathways, corroborating its role in regulating protein homeostasis. In addition, QRICH1 knockdown effectively restores cellular function in vitro. Adeno-associated virus (AAV)-mediated Qrich1 knockdown mitigates alveolar bone loss while suppressing ER stress and NF-κB activation. Collectively, these findings reveal that QRICH1 drives PDLSC dysfunction by enhancing NF-κB signaling and UPR-mediated apoptosis, highlighting its therapeutic potential in diabetic periodontitis.