{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:28:08Z","timestamp":1784215688706,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundamental Research Funds for the Central Universities, South-Central Minzu University","award":["CZQ22011"],"award-info":[{"award-number":["CZQ22011"]}]},{"name":"Fundamental Research Funds for the Central Universities, South-Central Minzu University","award":["81872755"],"award-info":[{"award-number":["81872755"]}]},{"name":"Fundamental Research Funds for the Central Universities, South-Central Minzu University","award":["82073714"],"award-info":[{"award-number":["82073714"]}]},{"name":"Fundamental Research Funds for the Central Universities, South-Central Minzu University","award":["MZR20008"],"award-info":[{"award-number":["MZR20008"]}]},{"name":"National Natural Science Foundation of China","award":["CZQ22011"],"award-info":[{"award-number":["CZQ22011"]}]},{"name":"National Natural Science Foundation of China","award":["81872755"],"award-info":[{"award-number":["81872755"]}]},{"name":"National Natural Science Foundation of China","award":["82073714"],"award-info":[{"award-number":["82073714"]}]},{"name":"National Natural Science Foundation of China","award":["MZR20008"],"award-info":[{"award-number":["MZR20008"]}]},{"name":"National Civil Affairs Commission\u2019s Young and Middle-Aged Talents Training Program","award":["CZQ22011"],"award-info":[{"award-number":["CZQ22011"]}]},{"name":"National Civil Affairs Commission\u2019s Young and Middle-Aged Talents Training Program","award":["81872755"],"award-info":[{"award-number":["81872755"]}]},{"name":"National Civil Affairs Commission\u2019s Young and Middle-Aged Talents Training Program","award":["82073714"],"award-info":[{"award-number":["82073714"]}]},{"name":"National Civil Affairs Commission\u2019s Young and Middle-Aged Talents Training Program","award":["MZR20008"],"award-info":[{"award-number":["MZR20008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Atraric acid (AA) is derived from lichens and is widely used in perfumes for its desirable scent. It has been reported as having anti-inflammatory and antioxidant activity. Hyperpigmentation is the underlying cause of a variety of dermatological diseases that have a significant impact on patients\u2019 quality of life and are frequently difficult to treat. This study aimed to explore the inhibitory effects of AA on hyperpigmentation in vitro and in vivo and its potential molecular mechanisms. The cytological results revealed that at a dose of 250 \u03bcM, AA may reduce melanin content and tyrosinase levels without causing cytotoxicity. Furthermore, the expression of melanocortin-1 receptor (MC1R), phosphorylated protein kinase A (pPKA) and phosphorylated cAMP response element binding protein (pCREB) were downregulated in AA-administrated cells. In vivo, histological analysis showed that AA could inhibit melanin production and tyrosinase activity, and 3% AA had the best activity, with almost no side effects. Furthermore, the results of Western blot analysis and RT-PCR suggested that AA may suppress the mRNA transcription of microphthalmia-associated transcription factor (MITF) protein and tyrosine protease by decreasing the expression of MC1R, consequently decreasing the phosphorylation of PKA and CREB. Finally, the MC1R inhibitor MSG606 verified the hypothesis that AA suppresses melanin formation by downregulating the PKA\/CREB\/MITF signaling pathway. Taken together, our study offers valuable information for the development of AA as a possible ingredient in skin-lightening cosmeceuticals and hyperpigmentation inhibitors.<\/jats:p>","DOI":"10.3390\/ijms232415952","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T03:01:51Z","timestamp":1671073311000},"page":"15952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Atraric Acid Ameliorates Hyperpigmentation through the Downregulation of the PKA\/CREB\/MITF Signaling Pathway"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3209-8973","authenticated-orcid":false,"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengping","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyun","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/0020-711X(87)90095-4","article-title":"Mammalian tyrosinase--the critical regulatory control point in melanocyte pigmentation","volume":"19","author":"Hearing","year":"1987","journal-title":"Int. J. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/1523-1747.ep12392743","article-title":"High-molecular-weight forms of tyrosinase and the tyrosinase-related proteins: Evidence for a melanogenic complex","volume":"103","author":"Orlow","year":"1994","journal-title":"J. Investig. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1152\/physrev.00044.2003","article-title":"Melanin pigmentation in mammalian skin and its hormonal regulation","volume":"84","author":"Slominski","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"D\u2019Mello, S.A., Finlay, G.J., Baguley, B.C., and Askarian-Amiri, M.E. (2016). Signaling Pathways in Melanogenesis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071144"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7643","DOI":"10.1002\/jcb.27112","article-title":"Effect of 3,6-anhydro-l-galactose on \u03b1-melanocyte stimulating hormone-induced melanogenesis in human melanocytes and a skin-equivalent model","volume":"119","author":"Kim","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1006\/excr.2000.4803","article-title":"Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9","volume":"255","author":"Xu","year":"2000","journal-title":"Exp. Cell. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1002\/ijc.25182","article-title":"Interleukins 1alpha and 1beta secreted by some melanoma cell lines strongly reduce expression of MITF-M and melanocyte differentiation antigens","volume":"127","author":"Kholmanskikh","year":"2010","journal-title":"Int. J. Cancer."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20443","DOI":"10.3390\/ijms141020443","article-title":"Inhibition of melanogenesis by gallic acid: Possible involvement of the PI3K\/Akt, MEK\/ERK and Wnt\/\u03b2-catenin signaling pathways in B16F10 cells","volume":"14","author":"Su","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.cbi.2016.08.023","article-title":"Dihydromyricetin from Ampelopsis grossedentata inhibits melanogenesis through down-regulation of MAPK, PKA and PKC signaling pathways","volume":"258","author":"Huang","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3892\/etm.2020.8687","article-title":"Natural skin-whitening compounds for the treatment of melanogenesis (Review)","volume":"20","author":"Qian","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1055\/a-0583-0410","article-title":"Plants and Natural Products for the Treatment of Skin Hyperpigmentation\u2014A Review","volume":"84","author":"Kanlayavattanakul","year":"2018","journal-title":"Planta. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Silvestri, M., Bennardo, L., Zappia, E., Tamburi, F., Cameli, N., Cannarozzo, G., and Nistic\u00f2, S.P. (2021). Q-Switched 1064\/532 nm Laser with Picosecond Pulse to Treat Benign Hyperpigmentations: A Single-Center Retrospective Study. Appl. Sci., 11.","DOI":"10.3390\/app11167478"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1017\/S0024282915000195","article-title":"Lichen Secondary Metabolites: Bioactive Properties and Pharmaceutical Potential","volume":"47","author":"Hawksworth","year":"2015","journal-title":"Lichenologist"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1080\/14786419.2018.1489386","article-title":"Chemical profile and biological activities of Peltigera horizontalis (Hudson) Baumg. thallus and apothecia extracts","volume":"34","year":"2020","journal-title":"Nat. Prod. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e202200134","DOI":"10.1002\/cbdv.202200134","article-title":"Anti-Inflammatory Potential of Compounds Isolated from Tunisian Lichens Species","volume":"19","author":"Mendili","year":"2022","journal-title":"Chem. Biodivers."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mun, S.K., Kang, K.Y., Jang, H.Y., Hwang, Y.H., Hong, S.G., Kim, S.J., Cho, H.W., Chang, D.J., Hur, J.S., and Yee, S.T. (2020). Atraric Acid Exhibits Anti-Inflammatory Effect in Lipopolysaccharide-Stimulated RAW264.7 Cells and Mouse Models. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197070"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1080\/14756366.2016.1256882","article-title":"Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors","volume":"32","author":"Pillaiyar","year":"2017","journal-title":"J. Enzyme. Inhib. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"814659","DOI":"10.3389\/fcimb.2021.814659","article-title":"Protein Tyrosine and Serine\/Threonine Phosphorylation in Oral Bacterial Dysbiosis and Bacteria-Host Interaction","volume":"11","author":"Ren","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1034\/j.1600-0749.13.s8.28.x","article-title":"The melanocortin-1 receptor is a key regulator of human cutaneous pigmentation","volume":"13","author":"Scott","year":"2000","journal-title":"Pigment Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12222","DOI":"10.3390\/ijms140612222","article-title":"UV Radiation and the Skin","volume":"14","author":"Jarrett","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lee, S.W., Kim, J.H., Song, H., Seok, J.K., Hong, S.S., and Boo, Y.C. (2019). Luteolin 7-Sulfate Attenuates Melanin Synthesis through Inhibition of CREB-and MITF-Mediated Tyrosinase Expression. Antioxidants, 8.","DOI":"10.3390\/antiox8040087"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1111\/pcmr.12986","article-title":"Management of Hyperpigmentation: Current Treatments and Emerging Therapies","volume":"34","author":"Nautiyal","year":"2021","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0923-1811(96)00575-0","article-title":"Comparison of the melanogenesis in human black and light brown melanocytes","volume":"14","author":"Maeda","year":"1997","journal-title":"J. Dermatol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"April, C.S., and Barsh, G.S. (2007). Distinct pigmentary and melanocortin 1 receptor-dependent components of cutaneous defense against ultraviolet radiation. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030009"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14958","DOI":"10.1038\/s41598-018-33352-8","article-title":"Beauvericin inhibits melanogenesis by regulating cAMP\/PKA\/CREB and LXR-\u03b1\/p38 MAPK-mediated pathways","volume":"8","author":"Lee","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ko, S.C., and Lee, S.H. (2021). Protocatechuic Aldehyde Inhibits \u03b1-MSH-Induced Melanogenesis in B16F10 Melanoma Cells via PKA\/CREB-Associated MITF Downregulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083861"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wu, K.C., Hseu, Y.C., Shih, Y.C., Sivakumar, G., Syu, J.T., Chen, G.L., Lu, M.T., and Chu, P.C. (2022). Calycosin, a Common Dietary Isoflavonoid, Suppresses Melanogenesis through the Downregulation of PKA\/CREB and p38 MAPK Signaling Pathways. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031358"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"819086","DOI":"10.3389\/fmicb.2022.819086","article-title":"Cloning and Functional Characterization of the Polyketide Synthases Based on Genome Mining of Preussia isomera XL-1326","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.phymed.2013.04.015","article-title":"Inhibitory effects of salidroside and paeonol on tyrosinase activity and melanin synthesis in mouse B16F10 melanoma cells and ultraviolet B-induced pigmentation in guinea pig skin","volume":"20","author":"Peng","year":"2013","journal-title":"Phytomedicine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jdermsci.2015.03.013","article-title":"Andrographolide suppresses melanin synthesis through Akt\/GSK3\u03b2\/\u03b2-catenin signal pathway","volume":"79","author":"Zhu","year":"2015","journal-title":"J. Dermatol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108862","DOI":"10.1016\/j.jnutbio.2021.108862","article-title":"Lycopene ameliorates insulin resistance and increases muscle capillary density in aging via activation of SIRT1","volume":"99","author":"Li","year":"2022","journal-title":"J. Nutr. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15952\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:41:42Z","timestamp":1760146902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15952"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,15]]},"references-count":31,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232415952"],"URL":"https:\/\/doi.org\/10.3390\/ijms232415952","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,15]]}}}