Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics

Luo，Piao1,2,5; Chen，Jiayun2; Zhang，Qian1,2,5; Xia，Fei2; Wang，Chen2; Bai，Yunmeng1; Tang，Huan2; Liu，Dandan2; Gu，Liwei2; Du，Qingfeng5; Xiao，Wei3,4; Yang，Chuanbin1; Wang，Jigang1,2,6

2022-12-01

10.1093/pcmedi/pbac023

Precision Clinical Medicine   Impact Factor & Quartile

2096-5303

2516-1571

Background: Aristolochic acids (AAs), a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants, are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma. Recently, accumulating evidence suggests that exposure to AAs could also induce hepatotoxicity and even hepatocellular carcinoma, though the mechanisms are poorly defined. Methods: Here, we aimed to dissect the underlying cellular and molecular mechanisms of aristolochic acid I (AAI)-induced hepatotoxicity by using advanced single-cell RNA sequencing (scRNA-seq) and proteomics techniques. We established the first single-cell atlas of mouse livers in response to AAI. Results: In hepatocytes, our results indicated that AAI activated NF-κB and STAT3 signaling pathways, which may contribute to the inflammatory response and apoptosis. In liver sinusoidal endothelial cells (LSECs), AAI activated multiple oxidative stress and inflammatory associated signaling pathways and induced apoptosis. Importantly, AAI induced infiltration of cytotoxic T cells and activation of proinflammatory macrophage and neutrophil cells in the liver to produce inflammatory cytokines to aggravate inflammation. Conclusions: Collectively, our study provides novel knowledge of AAs-induced molecular characteristics of hepatotoxicity at a single-cell level and suggests future treatment options for AAs associated hepatotoxicity.

aristolochic acid hepatotoxicity proteomics scRNA-seq

ESCI

English

First ; Corresponding

National Natural Science Foundation of China[81841001];National Natural Science Foundation of China[82074098];

WOS:000878763300001

2-s2.0-85145241347

Scopus

1.Department of Geriatric Medicine,Shenzhen People's Hospital,The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,518020,China
2.Artemisinin Research Center,Institute of Chinese Materia Medica,Chinese Academy of Chinese Medical Sciences,Beijing,100700,China
3.Key Laboratory of Glucolipid Metabolic Disorder,Ministry of Education,Guangdong Pharmaceutical University,Guangzhou,510006,China
4.Department of Nephrology,Integrated Hospital of Traditional Chinese Medicine,Southern Medical University,Guangzhou,510315,China
5.School of Traditional Chinese Medicine,Southern Medical University,Guangzhou,510515,China
6.Center for Reproductive Medicine,Dongguan Maternal and Child Health Care Hospital,Southern Medical University,Dongguan,523125,China

Luo，Piao,Chen，Jiayun,Zhang，Qian,et al. Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics[J]. Precision Clinical Medicine,2022,5(4).

Luo，Piao.,Chen，Jiayun.,Zhang，Qian.,Xia，Fei.,Wang，Chen.,...&Wang，Jigang.(2022).Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics.Precision Clinical Medicine,5(4).

Luo，Piao,et al."Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics".Precision Clinical Medicine 5.4(2022).