{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:58:21Z","timestamp":1781161101503,"version":"3.54.1"},"reference-count":44,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Technology Development Program","award":["RS-2024-00421318"],"award-info":[{"award-number":["RS-2024-00421318"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Sensitive skin is characterized by hypersensitivity to normal stimuli, and objective diagnostic tools and treatments are still limited. Currently, cosmetics for sensitive skin are developed through the exclusion of known irritants rather than investigation into the underlying mechanisms of sensitivity. In this study, we developed an integrated pipeline combining transcriptome analysis via microneedle-based skin sampling (MISSM), bioinformatics, in vitro validation, and clinical assessment to identify sensitive skin-associated inflammatory biomarkers and cosmetic ingredients that regulate them. Candidate biomarkers and matched cosmetic ingredients were identified from transcriptomic data and validated in lactic acid-stimulated HaCaT and human dermal fibroblasts via qRT-PCR. A prototype emulsion was developed and evaluated in a 4-week open-label pilot clinical trial with longitudinal molecular monitoring via MISSM. After lactic acid stimulation, sensitive skin-associated biomarkers (MCOLN1, CYR61, PMAIP1, PTGS2, and HMGB2) were significantly upregulated in both cell types, and cosmetic ingredients that regulate these biomarkers were confirmed in vitro. The emulsion prototype demonstrated hypoallergenicity in a primary irritation test. In the pilot clinical trial, target biomarker expression was significantly reduced in MISSM-derived samples, with improvements in skin hydration, barrier function, redness, and sensory reactivity also observed. This integrated pipeline will enable the discovery of inflammatory biomarker-regulating cosmetic ingredients, with potential applicability to various inflammatory skin conditions.<\/jats:p>","DOI":"10.3390\/biom16060843","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:50:58Z","timestamp":1781157058000},"page":"843","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sensitive Skin Improvement Through Bioinformatics-Identified Cosmetic Ingredients That Regulate Transcriptome-Derived Biomarkers"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3720-2509","authenticated-orcid":false,"given":"Seo Hyeong","family":"Kim","sequence":"first","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2734-1174","authenticated-orcid":false,"given":"Ji Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Min","family":"Shin","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Mi","family":"Choi","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da Som","family":"Kim","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Min","family":"Seo","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Young","family":"Jang","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Jae","family":"Lee","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2768-0825","authenticated-orcid":false,"given":"Jin-Muk","family":"Lim","sequence":"additional","affiliation":[{"name":"Precision Medicine Institute, Innowl Co., Ltd., Seoul 07801, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minsoo","family":"Han","sequence":"additional","affiliation":[{"name":"AI Institute, Alopax-Algo Co., Ltd., Seoul 07801, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1856-2998","authenticated-orcid":false,"given":"Do Hyeon","family":"Jeong","sequence":"additional","affiliation":[{"name":"Raphas Co., Ltd., Seoul 07793, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4361-1819","authenticated-orcid":false,"given":"Kwang Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Cutis Biomedical Research Center Co., Ltd., Seoul 07327, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1468-2494.2012.00754.x","article-title":"Sensitive skin: An overview","volume":"35","author":"Berardesca","year":"2013","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/jdv.15985","article-title":"Triggering factors in sensitive skin from the worldwide patients\u2019 point of view: A systematic literature review and meta-analysis","volume":"34","author":"Brenaut","year":"2020","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2340\/00015555-2397","article-title":"Definition of Sensitive Skin: An Expert Position Paper from the Special Interest Group on Sensitive Skin of the International Forum for the Study of Itch","volume":"97","author":"Misery","year":"2017","journal-title":"Acta Derm. Venereol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s40257-019-00499-7","article-title":"Sensitive Skin Syndrome: An Update","volume":"21","author":"Do","year":"2020","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1111\/j.1468-3083.2008.03037.x","article-title":"Sensitive skin in Europe","volume":"23","author":"Misery","year":"2009","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1046\/j.1365-2133.2001.04343.x","article-title":"Sensitive skin: An epidemiological study","volume":"145","author":"Willis","year":"2001","journal-title":"Br. J. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1600-0536.2009.01697.x","article-title":"Sensitive skin: Closing in on a physiological cause","volume":"62","author":"Farage","year":"2010","journal-title":"Contact Dermat."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bialas, I., Zelent-Kraciuk, S., and Jurowski, K. (2023). The Skin Sensitisation of Cosmetic Ingredients: Review of Actual Regulatory Status. Toxics, 11.","DOI":"10.3390\/toxics11040392"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jdermsci.2023.12.002","article-title":"The novel adiponectin receptor agonist APN5N alleviates sensitive skin by upregulating adiponectin expression","volume":"113","author":"Kim","year":"2024","journal-title":"J. Dermatol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xiao, T., Sun, M., Zhao, C., and Kang, J. (2023). TRPV1: A promising therapeutic target for skin aging and inflammatory skin diseases. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1037925"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/ics.12283","article-title":"Brief analysis of causes of sensitive skin and advances in evaluation of anti-allergic activity of cosmetic products","volume":"38","author":"Fan","year":"2016","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_12","first-page":"17","article-title":"Objective biophysical findings in patients with sensitive skin","volume":"31","author":"Zafiriou","year":"2005","journal-title":"Drugs Exp. Clin. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1111\/srt.13135","article-title":"Minimally invasive skin sampling and transcriptome analysis using microneedles for skin type biomarker research","volume":"28","author":"Kim","year":"2022","journal-title":"Ski. Res. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1021\/acs.chemrestox.3c00396","article-title":"In Silico Prediction of Skin Sensitization for Compounds via Flexible Evidence Combination Based on Machine Learning and Dempster-Shafer Theory","volume":"37","author":"Wang","year":"2024","journal-title":"Chem. Res. Toxicol."},{"key":"ref_15","first-page":"655771","article-title":"In silico Prediction of Skin Sensitization: Quo vadis? Front","volume":"12","author":"Ta","year":"2021","journal-title":"Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yeh, S.J., Lin, J.F., and Chen, B.S. (2021). Multiple-Molecule Drug Design Based on Systems Biology Approaches and Deep Neural Network to Mitigate Human Skin Aging. Molecules, 26.","DOI":"10.3390\/molecules26113178"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"575","DOI":"10.25259\/IJDVL_118_2023","article-title":"Three-part scoring system (tripartite) for teledermatology versus International Contact Dermatitis Research Group criteria to interpret patch test readings: A comparative, observational study","volume":"90","author":"Jasly","year":"2024","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.0105-1873.2005.00653.x","article-title":"The complex problem of sensitive skin","volume":"53","author":"Marriott","year":"2005","journal-title":"Contact Dermat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e13908","DOI":"10.1111\/srt.13908","article-title":"Development of a biomarker-based platform for comprehensive skin characterization using minimally invasive skin sampling and quantitative real-time PCR","volume":"30","author":"Kim","year":"2024","journal-title":"Ski. Res. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12109","DOI":"10.1038\/ncomms12109","article-title":"MCOLN1 is a ROS sensor in lysosomes that regulates autophagy","volume":"7","author":"Zhang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"108675","DOI":"10.1016\/j.cbi.2019.05.041","article-title":"Transcriptomic analyses reveal the molecular mechanisms of schisandrin B alleviates CCl4-induced liver fibrosis in rats by RNA-sequencing","volume":"309","author":"Zhang","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3858\/emm.2012.44.4.024","article-title":"A high concentration of genistein down-regulates activin A, Smad3 and other TGF-\u03b2 pathway genes in human uterine leiomyoma cells","volume":"44","author":"Di","year":"2012","journal-title":"Exp. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"M110.002170","DOI":"10.1074\/mcp.M110.002170","article-title":"Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein","volume":"10","author":"Sotoca","year":"2011","journal-title":"Mol. Cell. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3390\/brainsci5010014","article-title":"Microarray analysis reveals higher gestational folic Acid alters expression of genes in the cerebellum of mice offspring\u2014A pilot study","volume":"5","author":"Barua","year":"2015","journal-title":"Brain Sci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tan, W.S., Arulselvan, P., Ng, S.F., Mat Taib, C.N., Sarian, M.N., and Fakurazi, S. (2019). Improvement of diabetic wound healing by topical application of Vicenin-2 hydrocolloid film on Sprague Dawley rats. BMC Complement. Altern. Med., 19.","DOI":"10.1186\/s12906-018-2427-y"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.tiv.2015.09.015","article-title":"The organic osmolyte betaine induces keratin 2 expression in rat epidermal keratinocytes\u2014A genome-wide study in UVB irradiated organotypic 3D cultures","volume":"30","author":"Rauhala","year":"2015","journal-title":"Toxicol. Vitr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.det.2008.03.007","article-title":"Understanding and treating various skin types: The Baumann Skin Type Indicator","volume":"26","author":"Baumann","year":"2008","journal-title":"Dermatol. Clin."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1053\/ajcd.1997.2752","article-title":"Sensitive skin: Perceptions, evaluation, and treatment","volume":"8","author":"Draelos","year":"1997","journal-title":"Am. J. Contact Dermat."},{"key":"ref_29","first-page":"1","article-title":"Sensitive Skin Syndromes and Transient Receptors Potential (TRP) Channels in Sensitive Skin","volume":"3","author":"Chan","year":"2018","journal-title":"Int. J. Clin. Exp. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e13647","DOI":"10.1111\/srt.13647","article-title":"Microneedles: A novel clinical technology for evaluating skin characteristics","volume":"30","author":"Kim","year":"2024","journal-title":"Ski. Res. Technol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00424-005-1469-4","article-title":"Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2)","volume":"451","author":"Qian","year":"2005","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/ncb3114","article-title":"Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB","volume":"17","author":"Medina","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pitake, S., Middleton, L.J., Abdus-Saboor, I., and Mishra, S.K. (2019). Inflammation Induced Sensory Nerve Growth and Pain Hypersensitivity Requires the N-Type Calcium Channel Cav2.2. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01009"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chelombitko, M.A., Chernyak, B.V., Fedorov, A.V., Zinovkin, R.A., Razin, E., and Paruchuru, L.B. (2020). The Role Played by Mitochondria in Fc\u03b5RI-Dependent Mast Cell Activation. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.584210"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Pavlyuchenkova, A.N., Smirnov, M.S., Chernyak, B.V., and Chelombitko, M.A. (2024). The Role Played by Autophagy in Fc\u03b5RI-Dependent Activation of Mast Cells. Cells, 13.","DOI":"10.3390\/cells13080690"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"43310","DOI":"10.1038\/srep43310","article-title":"CCN1 promotes IL-1\u03b2 production in keratinocytes by activating p38 MAPK signaling in psoriasis","volume":"7","author":"Sun","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Fahey, E., and Doyle, S.L. (2019). IL-1 Family Cytokine Regulation of Vascular Permeability and Angiogenesis. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01426"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"24953","DOI":"10.1074\/jbc.M003040200","article-title":"Adhesion of human skin fibroblasts to Cyr61 is mediated through integrin \u03b16\u03b21 and cell surface heparan sulfate proteoglycans","volume":"275","author":"Chen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"44166","DOI":"10.1074\/jbc.M406813200","article-title":"Identification of a novel integrin \u03b1v\u03b23 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells","volume":"279","author":"Chen","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1083\/jcb.200608070","article-title":"Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa","volume":"176","author":"Naik","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R1064","DOI":"10.1152\/ajpregu.00538.2015","article-title":"Cutaneous vascular and sweating responses to intradermal administration of prostaglandin E1 and E2 in young and older adults: A role for nitric oxide?","volume":"310","author":"Fujii","year":"2016","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1080\/10739680802091526","article-title":"Nitric oxide and prostaglandin inhibition during acetylcholine-mediated cutaneous vasodilation in humans","volume":"15","author":"Medow","year":"2008","journal-title":"Microcirculation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1758835920970850","DOI":"10.1177\/1758835920970850","article-title":"Biological functions and theranostic potential of HMGB family members in human cancers","volume":"12","author":"Niu","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eads8597","DOI":"10.1126\/sciadv.ads8597","article-title":"Targeting HMGB2 acts as dual immunomodulator by bolstering CD8+ T cell function and inhibiting tumor growth in hepatocellular carcinoma","volume":"11","author":"Qu","year":"2025","journal-title":"Sci. Adv."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/843\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:25:04Z","timestamp":1781159104000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/843"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["biom16060843"],"URL":"https:\/\/doi.org\/10.3390\/biom16060843","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]}}}