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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\u2013epidermal 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.<\/jats:p>","DOI":"10.3390\/biology14070876","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T15:15:54Z","timestamp":1752765354000},"page":"876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dynamic Network Driver Analysis Identifies Master Factors Associated with Progression of Solar Lentigines"],"prefix":"10.3390","volume":"14","author":[{"given":"Deyu","family":"Cai","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China"},{"name":"Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Unilever Research & Development Centre Shanghai, Shanghai 200335, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8764-2521","authenticated-orcid":false,"given":"Chengming","family":"Zhang","sequence":"additional","affiliation":[{"name":"International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Xiao","sequence":"additional","affiliation":[{"name":"Unilever Research & Development Centre Shanghai, Shanghai 200335, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Cui","sequence":"additional","affiliation":[{"name":"Unilever Research & Development Centre Shanghai, Shanghai 200335, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3319-4135","authenticated-orcid":false,"given":"Xuelan","family":"Gu","sequence":"additional","affiliation":[{"name":"Unilever Research & Development Centre Shanghai, Shanghai 200335, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luonan","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China"},{"name":"Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China"},{"name":"School of Mathematical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China"},{"name":"School of Artificial Intelligence, Shanghai Jiao Tong University, Shanghai 200240, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1096\/fj.06-6649rev","article-title":"Human Skin Pigmentation: Melanocytes Modulate Skin Color in Response to Stress","volume":"21","author":"Costin","year":"2007","journal-title":"FASEB J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1365-2133.2006.07210.x","article-title":"Alterations in the Epidermal-Dermal Melanin Axis and Factor XIIIa Melanophages in Senile Lentigo and Ageing Skin","volume":"155","author":"Unver","year":"2006","journal-title":"Br. 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