Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives

Mitochondria have long been viewed as the "powerhouses" of the cell, but research over the past decade has established that they play a far more complex role in skin immune homeostasis beyond ATP production. The metabolic preferences of immune cells and skin parenchymal cells-glycolysis, oxidative phosphorylation, or fatty acid oxidation-determine their fate choices during inflammatory responses. When mitochondrial function is impaired, the release of damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and mitochondrial ROS can activate the cGAS-STING and NOD-like receptor family pyrin domain-containing 3 inflammasome pathways, driving inflammatory cycles in various skin diseases including psoriasis, atopic dermatitis, lupus erythematosus, and vitiligo. This review systematically examines the key mechanisms of mitochondrial metabolic reprogramming in skin immune disorders, focusing on 3 typical scenarios: the metabolic preferences of immune cells, mitochondrial DAMP-mediated autoinflammation, and the impact of mitochondrial dynamics imbalance on tissue-resident memory T cell function. Furthermore, we evaluate clinical evidence for repurposing old drugs such as metformin and thiazolidinediones, and discuss the translational prospects of emerging strategies including Nrf2 agonists, mitophagy inducers, and targeted nanocarriers. Understanding the "dual identity" of mitochondria in skin immunity-as both metabolic regulators and signaling sensors-will lay the foundation for developing precise metabolic immunomodulatory therapies.