Metabolic reprogramming and ferroptosis in keloid pathogenesis: new insights for targeted therapy.

Keloids are persistent fibroproliferative scars with an incompletely understood pathogenesis, traditionally linked to pathways such as TGF-β signaling and chronic inflammation. This review synthesizes recent literature focusing on the emerging roles of metabolic reprogramming and ferroptosis resistance in keloid fibroblasts. Recent studies highlight the convergence of these two processes as central factors sustaining the persistence and therapeutic resistance of these cells. Keloid fibroblasts exhibit cancer-like metabolic reprogramming, marked by a shift toward aerobic glycolysis, mitochondrial dysfunction, and disrupted lipid metabolism. This metabolic reorganization not only reflects the fibrotic process but also serves as a key driver of the fibroblasts' hyperproliferative, invasive, and matrix-producing characteristics. Concurrently, these fibroblasts display significant resistance to ferroptosis, an iron-dependent regulated cell death mechanism, acting as a critical survival strategy. Mechanistically, enhanced glycolysis supplies the reducing equivalents required to sustain the GPX4 antioxidant system, thereby preventing ferroptosis by neutralizing lipid peroxidation. Recognizing this integrated metabolic-ferroptotic axis shifts the therapeutic paradigm from symptomatic management to targeted, mechanism-based strategies. Interventions targeting critical nodes, such as glycolytic enzymes, or inducing ferroptosis with agents like ALA-PDT, present promising approaches to dismantle the survival advantages of keloid fibroblasts. These novel strategies offer the potential for more durable disease control, providing a foundation to overcome current translational challenges in drug delivery.