Archives of oral biology · 2025
ZBP1-NLRP3 axis integrates PANoptosis and ferroptosis during inflammatory injury in human dental pulp fibroblasts.
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He Ai-E, Wang Xing, Xie Ni, Xiao Yun-He
Аннотация
OBJECTIVE: To define how Z-DNA binding protein 1 (ZBP1) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling regulate lipopolysaccharide (LPS)-induced inflammation, PANoptosis, and ferroptosis in human dental pulp fibroblasts (HDPFs).
DESIGN: HDPFs were treated with LPS, and ZBP1 and NLRP3 were silenced using small interfering RNA (siRNA), individually or in combination. Inflammatory mediators and death-pathway markers were quantified by quantitative real-time PCR (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and biochemical assays; Annexin V/propidium iodide flow cytometry assessed cell-death distributions. RESULTS：: LPS significantly increased ZBP1 and NLRP3 expression and elevated cytokine/chemokine release; each was attenuated by ZBP1 or NLRP3 knockdown, with the greatest reduction after dual silencing. LPS triggered PANoptosis, as indicated by increased Annexin V⁺/PI⁺ cell populations and upregulation of caspase-1, cleaved caspase-8, RIPK3, GSDMD, and p-MLKL/MLKL, which were significantly reduced by inhibition of the ZBP1-NLRP3 axis. Ferroptosis features were also evident after LPS, including impaired iron homeostasis (downregulated ferritin heavy chain 1 [FTH1] and ferroportin [FPN1] with Fe²⁺ accumulation), enhanced lipid peroxidation (upregulated ALOX15, LPCAT3, PTGS2 with increased malondialdehyde and lipid reactive oxygen species), and weakened antioxidant defenses (reduced glutathione peroxidase-4 [GPX4], solute carrier family 7 member 11 [SLC7A11], glutathione, and GPX4 activity). These changes were mitigated by single-gene silencing and most effectively by dual knockdown.
CONCLUSION: The ZBP1-NLRP3 axis acts upstream to coordinate LPS-induced PANoptosis and ferroptosis in HDPFs. Targeting this axis dampens inflammatory cell death and oxidative-metabolic dysregulation, highlighting a potential therapeutic strategy for pulpitis-related tissue injury.
DESIGN: HDPFs were treated with LPS, and ZBP1 and NLRP3 were silenced using small interfering RNA (siRNA), individually or in combination. Inflammatory mediators and death-pathway markers were quantified by quantitative real-time PCR (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and biochemical assays; Annexin V/propidium iodide flow cytometry assessed cell-death distributions. RESULTS：: LPS significantly increased ZBP1 and NLRP3 expression and elevated cytokine/chemokine release; each was attenuated by ZBP1 or NLRP3 knockdown, with the greatest reduction after dual silencing. LPS triggered PANoptosis, as indicated by increased Annexin V⁺/PI⁺ cell populations and upregulation of caspase-1, cleaved caspase-8, RIPK3, GSDMD, and p-MLKL/MLKL, which were significantly reduced by inhibition of the ZBP1-NLRP3 axis. Ferroptosis features were also evident after LPS, including impaired iron homeostasis (downregulated ferritin heavy chain 1 [FTH1] and ferroportin [FPN1] with Fe²⁺ accumulation), enhanced lipid peroxidation (upregulated ALOX15, LPCAT3, PTGS2 with increased malondialdehyde and lipid reactive oxygen species), and weakened antioxidant defenses (reduced glutathione peroxidase-4 [GPX4], solute carrier family 7 member 11 [SLC7A11], glutathione, and GPX4 activity). These changes were mitigated by single-gene silencing and most effectively by dual knockdown.
CONCLUSION: The ZBP1-NLRP3 axis acts upstream to coordinate LPS-induced PANoptosis and ferroptosis in HDPFs. Targeting this axis dampens inflammatory cell death and oxidative-metabolic dysregulation, highlighting a potential therapeutic strategy for pulpitis-related tissue injury.
Предметные рубрики MeSH
HumansNLR Family, Pyrin Domain-Containing 3 ProteinFerroptosisDental PulpLipopolysaccharidesFibroblastsReal-Time Polymerase Chain ReactionBlotting, WesternEnzyme-Linked Immunosorbent AssayRNA-Binding ProteinsDNA-Binding ProteinsSignal TransductionCells, CulturedInflammationRNA, Small InterferingFlow CytometryReceptor-Interacting Protein Serine-Threonine KinasesReactive Oxygen SpeciesCytokines