Lipid metabolism dysregulation in solar lentigo: a multi-system-level analysis reveals membrane instability and energy homeostasis disruption

Solar lentigo is a common hyperpigmented skin condition caused by chronic ultraviolet exposure, primarily affecting photoaged skin. While previous investigations focused on inflammatory and melanogenic mechanisms, the comprehensive role of lipid metabolism in pathogenesis remains unclear. We aimed to investigate systemic alterations in lipid metabolism and their contribution to solar lentigo development. We performed comprehensive analysis of RNA sequencing data from solar lentigo lesions and control skin samples (n=7 per group) using metabolic flux simulations, gene co-expression networks, and protein-protein interaction analysis. These multi-system approaches were integrated to identify coordinated alterations in lipid metabolic pathways. Solar lentigo samples exhibited coordinated inhibition of fatty acid elongation, acetyl-CoA carboxylase activity, and sphingolipid biosynthesis, alongside impaired cholesterol synthesis via reduced squalene epoxidase and 7-dehydrocholesterol reductase activity. Compensatory upregulation of phospholipid synthesis enzymes and dihydroceramide desaturases was observed. Pathway disruption and altered calcium signaling, indicating aberrant cellular energy metabolism and membrane integrity. These findings demonstrate that solar lentigo pathogenesis involves systematic lipid metabolism dysregulation beyond melanogenesis, causing membrane instability, energy homeostasis disruption and redox imbalance. The identification of specific metabolic bottlenecks reveals novel targets for lipid-based therapeutic approaches in pigmentary diseases.