Altered bile acid metabolism in skin tissues in response to ionizing radiation: deoxycholic acid (DCA) as a novel treatment for radiogenic skin injury

AbstractObjective Radiogenic skin injury (RSI) is a common complication during cancer radiotherapy or accidental exposure to radiation. The aim of this study is to investigate the metabolism of bile acids (BAs) and their derivatives during RSI.Methods Rat skin tissues were irradiated by an X-ray linear accelerator. The quantification of BAs and their derivatives were performed by liquid chromatography–mass spectrometry (LC–MS)-based quantitative analysis. Key enzymes in BA biosynthesis were analyzed from single-cell RNA sequencing (scRNA-Seq) data of RSI in the human patient and animal models. The in vivo radioprotective effect of deoxycholic acid (DCA) was detected in irradiated SD rats.Results Twelve BA metabolites showed significant differences during the progression of RSI. Among them, the levels of cholic acid (CA), DCA, muricholic acid (MCA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), glycohyodeoxycholic acid (GHCA), 12-ketolithocholic acid (12-ketoLCA) and ursodeoxycholic acid (UDCA) were significantly elevated in irradiated skin, whereas lithocholic acid (LCA), tauro-β-muricholic acid (Tβ-MCA) and taurocholic acid (TCA) were significantly decreased. Additionally, the results of scRNA-Seq indicated that genes involved in 7a-hydroxylation process, the first step in BA synthesis, showed pronounced alterations in skin fibroblasts or keratinocytes. The alternative pathway of BA synthesis is more actively altered than the classical pathway after ionizing radiation. In the model of rat radiogenic skin damage, DCA promoted wound healing and attenuated epidermal hyperplasia.Conclusions Ionizing radiation modulates the metabolism of BAs. DCA is a prospective therapeutic agent for the treatment of RSI.Keywords: Ionizing radiationskin injurybile acid metabolismdeoxycholic acid (DCA) AcknowledgementsThis study is supported by the National Natural Science Foundation of China (32071238, 82073477 and 82203973) and the Young Talent Project of the China National Nuclear Corporation and Scientific Fund for Distinguished Young Scholars in Sichuan Province (2022JDJQ0051). The authors would like to thank Dr. Qidong Zu (OE Biotech, Inc., Shanghai, China) for assistance with the bioinformatics analysis of scRNA-seq data.Author contributionsSZ and DY conceived and designed the study. WM and BS carried out the molecular biology studies. YZ and TY drafted the manuscript and the figures. YZ and FG performed the statistical analysis. ZH modified the manuscript. All authors read and approved the final manuscript.Disclosure statementSichuan University has one patent pending related to the radioprotective effective of DCA reported in this work, which entitled ‘DCA in treating inflammatory skin injury’.Data availability statementDatasets of scRNA-Seq in this study are accessible through GSE193564 and GSE193807. The mass spectrometry data are available through the MetaboLight public data repository via access number MTBLS7333.Additional informationFundingThis study is supported by the National Natural Science Foundation of China (32071238, 82073477 and 82203973), the Young Talent Project of China National Nuclear Corporation and the Scientific Fund for Distinguished Young Scholars in Sichuan Province (2022JDJQ0051). Notes on contributorsYining ZhangYining Zhang is a Student of West China School of Basic Medical Sciences and Forensic Medicine, which belongs to Sichuan University. The lab, which she studied, belongs to West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University.Tao YanTao Yan is a Junior Research Assistant at West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University.Wei MoWei Mo is a Postgraduate of State Key Lab of Radiation Medicine and Protection and School of Radiation Medicine and Protection, which belongs to Medical College of Soochow University.Bin SongBin Song is a Research Scientist in Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.Yuehua ZhangYuehua Zhang is a postdoctor in Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.Fenghao GengFenghao Geng is a Student of West China School of Basic Medical Sciences and Forensic Medicine, which belongs to Sichuan University. The lab, which he studied, belongs to West China Second University Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University.Zhimin HuZhimin Hu, Ph.D., Key Laboratory of Radiation Physics and Technology of Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu, China.Daojiang YuDaojiang Yu, Ph.D., Medical Director of Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital. He is a doctoral candidate at West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University.Shuyu ZhangShuyu Zhang, Ph.D., is Head of the Lab of Radiation Medicine, which both belongs to West China Second University Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University. Moreover, He is a Senior Researcher at Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital.