Objective ·To systematically compare the characteristics of long non-coding RNAs (lncRNAs) and their mediated competing endogenous RNA (ceRNA) regulatory networks in periodontitis (PD) and peri-implantitis (PI). Methods ·Twenty-four male SD rats were randomly divided into the control (CON), PD, and PI groups, with eight rats in each group. In the PD group, an experimental PD model was established by ligating the bilateral maxillary first molars with silk sutures. In the PI group, custom titanium implants were placed in the bilateral maxillary first molar regions, followed by silk ligation to induce PI. Gingival tissues from each group were collected for transcriptome sequencing to obtain expression profiles of lncRNAs and mRNAs. DESeq2 was used to screen differentially expressed lncRNAs and mRNAs. Weighted gene co-expression network analysis (WGCNA) was performed to identify module genes associated with PD and PI. Gene Ontology (GO) functional enrichment analysis of the module genes was conducted using KOBAS software. miRNA binding sites were predicted using miRanda software (score≥150), and lncRNA-miRNA-mRNA ceRNA regulatory networks associated with PD- and PI-related module genes were constructed. ceRNA regulatory axes related to PD and PI modules were screened. Results ·Compared with the CON group, 124 up-regulated and 406 down-regulated differentially expressed lncRNAs were identified in the PD group, while 43 up-regulated and 95 down-regulated differentially expressed lncRNAs were identified in the PI group. A total of 22 lncRNAs were differentially expressed in both PD and PI groups. Additionally, 508 lncRNAs were specifically differentially expressed in the PD group, and 116 in the PI group. WGCNA identified the lightcyan module significantly positively correlated with PD and the midnightblue module significantly positively correlated with PI. GO functional enrichment analysis showed that genes in the lightcyan module were significantly enriched in biological processes related to endoplasmic reticulum-associated degradation (ERAD) signaling and response to endoplasmic reticulum stress (ERS), whereas genes in the midnightblue module were significantly enriched in biological processes such as skin barrier formation, keratinocyte differentiation, and epithelial development. Based on these modules, ceRNA regulatory networks were constructed, revealing regulatory axes associated with ERS in the PD group, including ENSRNOG00000063579-miR-1249-Calr (calreticulin), ENSRNOG00000063579-miR-1249-Man1b1 (mannosidase α class 1B member 1), ENSRNOG00000063488-miR-328a-5p-Rnf183 (ring finger protein 183), and ENSRNOG00000063230-miR-3558-5p-Fbxo2 (F-box protein 2), as well as regulatory axes associated with skin barrier function in the PI group, including ENSRNOG00000067449-miR-238a-5p-Krt1 (keratin 1), ENSRNOG00000067449-miR-238a-5p-Krt16, ENSRNOG00000067625-miR-3541-Klf4 (Krüppel-like factor 4), and ENSRNOG00000067625-miR-667-5p-Tgm3 (transglutaminase 3). Conclusion ·This study reveals differences in lncRNA and mRNA expression profiles between PD and PI, suggesting that the two diseases are respectively associated with pathways related to ERS and skin barrier function. These findings provide a basis for understanding the molecular pathological characteristics of the two diseases.