Integrated plasma metabolomic and proteomic analysis uncover the effects and mechanisms of isotretinoin in severe acne

Manqi Xia¹Zhang Jing¹Yang Hu²Ziyan Chen¹Yanan Ke¹Shujuan Zhang¹Zeen Yang¹Xin Tian¹Jingyao Liang^1*Yumei Liu^1*

• ¹Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, China
• ²Qianxi People’s Hospital, Qianxi, China

Background: Acne vulgaris is a prevalent chronic inflammatory disorderof the skin and oral isotretinoin is one of the most effective treatments forsevere acne with incompletely understood mechanisms. The aim of thisstudy was to investigate the pathogenesis of acne and the therapeuticmechanisms underlying isotretinoin treatment from integrated human plasma metabolomics and proteomics.Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) full-spectrum metabolomics and four-dimensional data-independent acquisition (4D-DIA) quantitative proteomics were employed to analyze plasma samples from patients with group AG (severe acne group), group AG1 (severe acne group1, before isotretinoin treatment), group TG (isotretinoin treatment group) and group CG (control group). Bioinformatics statistical analysis were employed to analyze the metabolomic and proteomic data.Results: 489 differentially expressed metabolites (DEMs) were detected in the plasma from patients with severe acne compared to controls.Isotretinoin treatment normalized the dysregulation of 94 metabolites, including inositol 1,3,4-trisphosphate (Ins(1,3,4)P3), 11-cis-retinol, thyroxine (T4), androstenediol, estrone 3-sulfate, bovinicacid, n-oleoylethanolamine, LPS(20:1), Cer(d16:1/23:0) and TG(17:1 18:2 18:3). Additionally, 36 differentially expressed proteins (DEPs) were identified in patients before and after isotretinoin treatment. Notably, down-regulation of acyl-CoA synthetase long-chain family member 4 (ACSL4) suggests a potential therapeutic mechanism for isotretinoin, while up-regulation of monoacylglycerol O-acyltransferase 2 (MOGAT2) may mediate the elevation of blood lipids and the correction of some abnormal lipids. Isotretinoin modulates multiple pathways, including inositol phosphatemetabolism, glycerolipid metabolism, thyroid hormone synthesis and insulin resistance.Conclusions: Important DEMs, DEPs and metabolic pathways were identified in this study, which will help clarify the pathogenesis of acneand the potential mechanisms of isotretinoin in the treatment of acne, andidentify novel targets for severe acne treatment and side effect reduction.