Dynamic Network Driver Analysis Identifies Master Factors Associated with Progression of Solar Lentigines

Solar lentigines, commonly caused by prolonged ultraviolet exposure, raise the risk of skin disorders and remain challenging to manage due to their complex mechanisms. Understanding the molecular mechanisms driving the progression of solar lentigines is crucial for developing effective protective strategies. In this study, we introduced a novel method, Dynamic Network Driver (DND), which identifies upstream regulators that drive disease progression by integrating the Dynamic Network Biomarker (DNB) approach with network control theory. By applying DND to multi-omics data from solar lentigines subjects, we (1) identified the key drivers associated with solar lentigo progression, with their functions involved in differentiation and dermal-epidermal junction; and (2) highlighted ARNT2 and TBX2 as significant master factors supported by in vitro validation in melanocytes and pigmented 3D living skin equivalent models. These results demonstrate the potency of DND for uncovering the molecular mechanisms behind solar lentigines and informing therapeutic strategies. In summary, the DND approach identified novel drivers of solar lentigo progression, acting as new markers for spot mitigation in 3D spot mimic models.