Ferroptosis-Resistant Adipocytes Drive Keloid Pathogenesis via GPX4-Mediated Adipocyte-Mesenchymal Transition and Iron-Cystine Metabolic Communication.

Background: Keloids are a challenging fibrotic disorder with limited treatment options. The study sought to examine the underlying mechanisms of keloid pathogenesis, emphasizing the influence of dermal adipocytes and ferroptosis resistance in driving fibrosis. Methods: Single-cell RNA sequencing (scRNA-seq) was employed for determining essential cell populations in keloid tissue. Mechanistic studies assessed iron overload, Reactive Oxygen Species (ROS) exhaustion, and interferon responses in ferroptosis-resistant adipocytes. Glutathione peroxidase 4 (GPX4) expression and TGF-β signaling activation were evaluated in adipocyte-mesenchymal transition (AMT). Paracrine signaling and metabolic symbiosis between adipocytes and fibroblasts were analyzed. Therapeutic interventions (ferroptosis inducer RSL3 and iron chelator deferoxamine DFO) were tested in vivo. Results: Through single-cell RNA sequencing, we identified ferroptosis-resistant dermal adipocytes as key contributors to keloid pathogenesis, exhibiting iron overload, ROS suppression, and impaired interferon responses. These adipocytes demonstrated elevated GPX4 expression, which mechanistically drove AMT via iron-dependent activation of TGF-β signaling pathways. GPX4-activated adipocytes promoted fibroblast collagen production through paracrine signaling while establishing a metabolic symbiosis: adipocytes exported iron via solute carrier family 40 member 1 (SLC40A1) to neighboring fibroblasts, which reciprocally supplied cystine through cystathionine beta-synthase (CBS)/cystinosin, lysosomal cystine transporter (CTNS) to sustain GPX4 activity. This vicious cycle was further amplified by iron/ROS-mediated suppression of interferon signaling, creating a pro-fibrotic feedback loop. Therapeutic targeting with either the ferroptosis inducer RSL3 or iron chelator deferoxamine (DFO) effectively disrupted this pathological network, suppressing GPX4/AMT while restoring interferon responses and attenuating keloid growth in vivo. This study clarifies a new adipocyte-focused mechanism in keloid development and identifies ferroptosis regulation as a potential treatment approach for this persistent condition. Conclusions: This study reveals a novel adipocyte-centered mechanism in keloid pathogenesis driven by GPX4-mediated ferroptosis resistance, metabolic symbiosis, and disrupted interferon signaling. The findings establish ferroptosis modulation (via RSL3 or iron chelation) as a promising therapeutic strategy for keloids, offering potential new treatments for this recalcitrant condition.