GalNAc-siRNA conjugates mediate the silencing of the parasite-derived lncRNA: A novel therapeutic approach for liver fluke-induced liver fibrosis

Yangyuan Qiu; Xue Bai; Jingna Gao; Bin Tang; Mingyuan Liu; Jing Ding; Xiaolei Liu

doi:10.1016/j.ijbiomac.2025.145580

GalNAc-siRNA conjugates mediate the silencing of the parasite-derived lncRNA: A novel therapeutic approach for liver fluke-induced liver fibrosis

Int J Biol Macromol. 2025 Jun 26:145580. doi: 10.1016/j.ijbiomac.2025.145580. Online ahead of print.

Authors

Yangyuan Qiu¹, Xue Bai², Jingna Gao³, Bin Tang², Mingyuan Liu⁴, Jing Ding², Xiaolei Liu⁵

Affiliations

¹ State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China; Anhui Key Laboratory of Infection and Immunity, Department of Microbiology and Parasitology, Bengbu Medical University, Bengbu 233030, China.
² State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China.
³ Department of Pathology, The First Hospital of Jilin University, Changchun 130021, China.
⁴ State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China.
⁵ State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: liuxlei@163.com.

PMID: 40581025
DOI: 10.1016/j.ijbiomac.2025.145580

Abstract

Clonorchis sinensis, as a liver fluke, can cause chronic liver damage, liver fibrosis, and even cholangiocarcinoma (CCA). However, there is a lack of effective therapeutic approaches for the treatment of clonorchiasis. Thus, we aimed to investigate the role of long noncoding RNAs (lncRNAs) in liver fibrosis induced by C. sinensis and evaluate the therapeutic potential of GalNAc-modified siRNAs targeting these lncRNAs. In this study, we first isolated Clonorchis sinensis extracellular vesicles (CsEVs) and identified the fibrosis-related long noncoding RNA lnc28240.1 in the CsEVs. In vitro and in vivo experiments revealed that the CsEVs and lnc28240.1 could induce liver fibrosis. Thus, to inhibit the development of liver fibrosis, we designed and synthesized a short interfering RNA#1 (siRNA#1) modified with N-acetylgalactosamine (GalNAc) to silence the pathogenic gene lnc28240.1. The results demonstrated that the GalNAc-siRNA conjugates effectively silenced lnc28240.1, significantly reducing C. sinensis-induced liver fibrosis and normalizing liver function. Our findings suggest that GalNAc-siRNA for gene silencing of parasite-derived lncRNA is a promising therapeutic strategy for the treatment of liver fibrosis caused by C. sinensis.

Keywords: Clonorchis sinensis; N-acetylgalactosamine; Short interfering RNA.