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We isolated periodontal ligament stem cells from periodontitis patients and healthy controls (P-PDLSCs and H-PDLSCs). To further simulate the periodontal microenvironment in patients, lipopolysaccharide (LPS) was used to treat H-PDLSCs. The results showed that periodontitis-related inflammation gave rise to the upregulated expression levels of ER stress representative genes including GRP78, PERK, ATF4, and CHOP. In contrast, the treatment of 4-phenyl butyric acid (4-PBA) remarkably suppressed ER stress and supported cell viability. The increased secretion of proinflammatory factors like TNF-\u03b1, IL-1\u03b2, and IL-6 and the activation of NF-\u03baB pathway were also attenuated by 4-PBA treatment. Moreover, 4-PBA treatment restored the impaired osteogenic differentiation ability of PDLSCs, as demonstrated by the upregulated expression levels of Runx2 and OCN as well as the enhanced Alizarin red staining. 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