{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:07:20Z","timestamp":1790381240450,"version":"4.1.0"},"reference-count":82,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health (MoH)","award":["PNRR-MCNT2-2023-12377707"],"award-info":[{"award-number":["PNRR-MCNT2-2023-12377707"]}]},{"name":"Italian Ministry of Health (MoH)","award":["RC2025"],"award-info":[{"award-number":["RC2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Vitiligo is featured by the manifestation of white maculae and primarily results from inflammatory\/immune-selective aggression to melanocytes. The trigger mechanism leading to the activation of resident immune cells in the skin still lacks a molecular description. There is growing evidence linking altered mitochondrial metabolism to vitiligo, suggesting that an underlying metabolic defect may enable a direct activation of the immune system. Recent evidence demonstrated the association of vitiligo with disorders related to systemic metabolism, including insulin resistance (IR) and lipid disarrangements. However, IR, defined as a cellular defect in the insulin-mediated control of glucose metabolism, and its possible role in vitiligo pathogenesis has not been proven yet. Methods: In this study, we compared the Ins\/IGF-1 intracellular signaling of dermal and epidermal cells isolated from non-lesional vitiligo skin to that belonging to cells obtained from healthy donors. Results: We demonstrated that due to the intensified glucose uptake, S6, and insulin receptor substrate 1 (IRS1) chronic phosphorylation, their inducibilities were downsized, a condition that coincides with the definition of insulin resistance at the cellular level. Correspondingly, the mitogenic and metabolic activities normally provoked by Ins\/IGF-1 exposure resulted in significantly compromised vitiligo cells (p \u2264 0.05). Besides all the vitiligo-derived skin cells manifesting an energetic disequilibrium consisting of a low ATP, catabolic processes activation, and chronic oxidative stress, the functional consequences of this state appear amplified in the keratinocyte lineage. Conclusion: The presented data argue for insulin and IGF-1 resistance collocating dysfunctional glucose metabolism in the mechanisms of vitiligo pathogenesis. In vitiligo keratinocytes, the intrinsic impairment of intracellular metabolic activities, particularly when associated with stimulation with Ins\/IGF-1, converges into an aberrant pro-inflammatory phenotype that may initiate immune cell recruitment.<\/jats:p>","DOI":"10.3390\/cells14080565","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T05:28:07Z","timestamp":1744262887000},"page":"565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Defective Intracellular Insulin\/IGF-1 Signaling Elucidates the Link Between Metabolic Defect and Autoimmunity in Vitiligo"],"prefix":"10.3390","volume":"14","author":[{"given":"Silvia","family":"Caputo","sequence":"first","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Papaccio","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6640-7418","authenticated-orcid":false,"given":"Ramona","family":"Marrapodi","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Lopez","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Iacovelli","sequence":"additional","affiliation":[{"name":"Clinical Dermatology, Phototherapy Unit, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Pacifico","sequence":"additional","affiliation":[{"name":"Clinical Dermatology, Phototherapy Unit, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5316-8937","authenticated-orcid":false,"given":"Emilia","family":"Migliano","sequence":"additional","affiliation":[{"name":"Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Cota","sequence":"additional","affiliation":[{"name":"Genetic Research, Molecular Biology and Dermatopathology Unit, San Gallicano Dermatological Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5575-9968","authenticated-orcid":false,"given":"Anna","family":"Di Nardo","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Picardo","sequence":"additional","affiliation":[{"name":"Istituto Dermopatico dell\u2019Immacolata (IDI-IRCCS), 00167 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-5500","authenticated-orcid":false,"given":"Barbara","family":"Bellei","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.4103\/ijd.IJD_344_18","article-title":"Antimelanocyte Antibodies: A Possible Role in Patients with Vitiligo","volume":"65","author":"Helmy","year":"2020","journal-title":"Indian J. 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