International immunopharmacology · 2026
High-cholesterol-load-triggered pyroptosis of gingival fibroblasts promotes periodontitis.
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Wang Zhenxiang, Li Yueheng, Chen Hang, Zhang Xiaonan, Zhang Yumeng, Gao Xin, Luo Jun, Song Jinlin, Zhou Zhi
Аннотация
BACKGROUND: Periodontitis is a common inflammatory disease known to be closely associated with metabolic disorders. Studies have shown a positive correlation between serum cholesterol levels and the severity of periodontitis in patients, yet how cholesterol aggravates periodontal tissue damage remains unclear.
METHODS: Single-cell sequencing dataset of patients with periodontitis was analyzed to identify the potential role of cholesterol in periodontitis. A high-cholesterol diet (HCD) rat model was established, and gingival RNA sequencing was performed. Then, in vitro, gingival fibroblasts' (GFs) pyroptotic ratio and NLRP3-mediated pyroptosis pathway activation were analyzed under cholesterol and pyroptosis inhibitors. Further mechanistic studies identified this activation was triggered by cholesterol-induced lysosomal injury and subsequent cathepsin B (CTSB) release. Finally, the therapeutic efficacy of NLRP3 and CTSB inhibitors was confirmed in the periodontitis rat model.
RESULTS: Single-cell analysis indicated that GFs displayed the strongest cholesterol-response gene signature among periodontal cell types. Gingival transcriptomics from HCD rats showed enrichment of NLRP3/pyroptosis pathways. In cholesterol-treated GFs, lysosomal membrane permeabilization (LMP) occurred with cytosolic CTSB release, accompanied by robust activation of the NLRP3-Caspase1-GSDMD axis and increased pyroptosis. CA074me reduced CTSB activity, inflammasome activation, and GF pyroptosis, and NLRP3 inhibition produced similar effects of inhibiting inflammation. In experimental periodontitis, targeting CTSB or NLRP3 mitigated GF pyroptosis and alleviated alveolar bone loss.
CONCLUSION: Cholesterol overload drives GF pyroptosis via lysosomal injury and CTSB-dependent activation of NLRP3, contributing to alveolar bone resorption. Inhibiting CTSB or NLRP3 may offer therapeutic strategies for experimental periodontitis.
METHODS: Single-cell sequencing dataset of patients with periodontitis was analyzed to identify the potential role of cholesterol in periodontitis. A high-cholesterol diet (HCD) rat model was established, and gingival RNA sequencing was performed. Then, in vitro, gingival fibroblasts' (GFs) pyroptotic ratio and NLRP3-mediated pyroptosis pathway activation were analyzed under cholesterol and pyroptosis inhibitors. Further mechanistic studies identified this activation was triggered by cholesterol-induced lysosomal injury and subsequent cathepsin B (CTSB) release. Finally, the therapeutic efficacy of NLRP3 and CTSB inhibitors was confirmed in the periodontitis rat model.
RESULTS: Single-cell analysis indicated that GFs displayed the strongest cholesterol-response gene signature among periodontal cell types. Gingival transcriptomics from HCD rats showed enrichment of NLRP3/pyroptosis pathways. In cholesterol-treated GFs, lysosomal membrane permeabilization (LMP) occurred with cytosolic CTSB release, accompanied by robust activation of the NLRP3-Caspase1-GSDMD axis and increased pyroptosis. CA074me reduced CTSB activity, inflammasome activation, and GF pyroptosis, and NLRP3 inhibition produced similar effects of inhibiting inflammation. In experimental periodontitis, targeting CTSB or NLRP3 mitigated GF pyroptosis and alleviated alveolar bone loss.
CONCLUSION: Cholesterol overload drives GF pyroptosis via lysosomal injury and CTSB-dependent activation of NLRP3, contributing to alveolar bone resorption. Inhibiting CTSB or NLRP3 may offer therapeutic strategies for experimental periodontitis.