Fibroblast Ferroptosis Aggravates Inflammation Response in Dental Pulpitis

Abstract

Introduction and aims

Pulpitis, an inflammatory disorder of dental pulp tissue, represents a common clinical challenge in endodontic pathology. Emerging evidence implicates ferroptosis, a newly recognised iron-dependent form of regulated cell death, in the pathogenesis of inflammatory conditions. However, its functional significance in pulpal inflammation remains poorly characterised. The objectives of this study were to (1) investigate the functional significance of ferroptosis in pulpitis; (2) identify the cell type undergoing ferroptosis; and (3) provide novel insights into therapeutic strategies.

Methods

We conducted an investigation combining clinical specimen analysis (human pulp tissues), single-cell transcriptomic profiling and experimental mice models. Co-localisation staining and single-cell RNA sequencing data were analysed to identify the cell type that underwent ferroptosis. Immunofluorescence co-localisation studies and scRNA-seq data analysis were used to identify cellular populations undergoing ferroptosis. The susceptibility of dental pulp fibroblasts to ferroptosis in an inflammatory condition was investigated using in vitro cell cultures.

Results

Our findings demonstrate that dental pulp fibroblasts undergo ferroptosis in pulpitis. Pulpitis-induced pro-inflammatory immune responses were characterised by a profound elevation of fibroblast-derived interleukin-6 (IL-6) and interleukin-1β (IL-1β), which was attenuated by ferroptosis inhibition. Pulp inflammation is alleviated by inhibition of fibroblast ferroptosis.

Conclusion

This study reveals a previously unrecognised mechanistic link between fibroblast ferroptosis and pulpal immunopathology, providing novel insights into therapeutic strategies for vital pulp preservation.

Clinical Significance

The identification of fibroblast ferroptosis as a driver of pulp inflammation and inhibition of inflammation by ferroptosis inhibitors Ferrostatin-1 (Fer-1) in mice models offer potential alternative therapeutic strategies for vital pulp preservation.