Ferroptosis-Resistant Adipocytes Drive Keloid Pathogenesis via GPX4-Mediated Adipocyte-Mesenchymal Transition and Iron-Cystine Metabolic Communication
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Summary
This summary is machine-generated.Keloid fibrosis is driven by ferroptosis-resistant adipocytes promoting collagen production. Targeting ferroptosis with inducers or iron chelators offers a promising new therapeutic strategy for keloids.
Area Of Science
- Fibrosis research
- Cellular metabolism
- Dermatology
Background
- Keloids represent a significant fibrotic disorder with limited therapeutic interventions.
- Understanding keloid pathogenesis is crucial, with a focus on dermal adipocytes and ferroptosis resistance.
- Investigating the interplay between adipocytes and fibroblasts in keloid formation is essential.
Purpose Of The Study
- To elucidate the mechanisms of keloid pathogenesis, particularly the role of dermal adipocytes.
- To examine the contribution of ferroptosis resistance in adipocytes to keloid fibrosis.
- To explore potential therapeutic strategies targeting ferroptosis pathways in keloids.
Main Methods
- Single-cell RNA sequencing (scRNA-seq) to identify key cell populations in keloid tissue.
- Mechanistic studies on iron overload, reactive oxygen species (ROS) exhaustion, and interferon responses in adipocytes.
- Evaluation of Glutathione peroxidase 4 (GPX4) expression and TGF-β signaling in adipocyte-mesenchymal transition (AMT); in vivo testing of ferroptosis inducer (RSL3) and iron chelator (DFO).
Main Results
- scRNA-seq identified ferroptosis-resistant adipocytes as key drivers of keloid pathogenesis, showing iron overload and impaired interferon responses.
- Elevated GPX4 expression in adipocytes promoted AMT via iron-dependent TGF-β signaling, enhancing fibroblast collagen production.
- A metabolic symbiosis between adipocytes and fibroblasts was observed, involving iron and cystine exchange, amplifying a pro-fibrotic feedback loop; RSL3 and DFO treatments attenuated keloid growth in vivo.
Conclusions
- A novel adipocyte-centered mechanism in keloid pathogenesis involves GPX4-mediated ferroptosis resistance, metabolic symbiosis, and disrupted interferon signaling.
- Ferroptosis modulation, through agents like RSL3 or iron chelation, presents a promising therapeutic strategy for recalcitrant keloid conditions.
- Targeting this adipocyte-fibroblast crosstalk offers a new avenue for developing effective keloid treatments.
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