Mitochondrial dysfunction promotes keloid progression through metabolic reprogramming: A narrative review.

Keloids are a refractory fibroproliferative disorder characterized by excessive extracellular matrix (ECM) deposition and invasive growth beyond the original wound boundaries, severely impairing patients' quality of life. Accumulating evidence highlights that metabolic reprogramming and mitochondrial dysfunction are important in keloid pathogenesis, particularly in regulating the biological behavior of keloid fibroblasts (KFBs). This narrative review focuses on the sustained development and progression of keloids rather than the triggering factors of disease initiation, and systematically reviews the latest research on the interplay between mitochondrial dysfunction and metabolic abnormalities in keloids. Mitochondrial structural and functional impairments directly trigger metabolic reprogramming in KFBs, shifting energy metabolism toward aerobic glycolysis and disrupting lipid and amino acid metabolism. Conversely, metabolic abnormalities exacerbate mitochondrial damage, forming a pathological feedback loop. This reciprocal interaction collectively shapes the pathological features of KFBs: excessive proliferation driven by energy metabolic adaptation, abnormal ECM deposition mediated by pro-fibrotic signaling activation, and persistent chronic inflammation induced by mitochondrial damage-associated molecular patterns (DAMPs) and metabolic byproducts. By clarifying this synergistic mechanism, this review provides insights into novel therapeutic strategies targeting mitochondrial function and metabolic pathways to mitigate keloid progression. Mechanistically, this revision further highlights that HIF-1α, PI3K/Akt/mTOR, AMPK, NOX4, Piezo1/YAP, NLRP3/STING, and lactate-dependent histone lactylation act as signaling hubs that connect mitochondrial injury to glycolysis, lipid remodeling, amino-acid flux, extracellular matrix (ECM) accumulation, apoptosis resistance, and chronic inflammation.