1. Academic Validation
  2. Cordycepin alleviates hepatic fibrosis in association with the inhibition of glutaminolysis to promote hepatic stellate cell senescence

Cordycepin alleviates hepatic fibrosis in association with the inhibition of glutaminolysis to promote hepatic stellate cell senescence

  • Int Immunopharmacol. 2024 May 10:132:111981. doi: 10.1016/j.intimp.2024.111981.
Zhu Liang 1 Keyan Zhang 1 Hongli Guo 2 Xujiao Tang 1 Mingzhu Chen 1 Jinsong Shi 1 Jing Yang 3
Affiliations

Affiliations

  • 1 School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China.
  • 2 Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.
  • 3 School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China. Electronic address: yangjing@jiangnan.edu.cn.
Abstract

Cordycepin (CRD) is an active component derived from Cordyceps militaris, which possesses multiple biological activities and uses in liver disease. However, whether CRD improves liver fibrosis by regulating hepatic stellate cell (HSC) activation has remained unknown. The study aims further to clarify the activities of CRD on liver fibrosis and elucidate the possible mechanism. Our results demonstrated that CRD significantly relieved hepatocyte injury and inhibited HSC activation, alleviating hepatic fibrogenesis in the Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC)-induced mice model. In vitro, CRD exhibited dose-dependent repress effects on HSC proliferation, migration, and pro-fibrotic function in TGF-β1-activated LX-2 and JS-1 cells. The functional enrichment analysis of RNA-seq data indicated that the pathway through which CRD alleviates HSC activation involves cellular senescence and cell cycle-related pathways. Furthermore, it was observed that CRD accumulated the number of senescence-associated a-galactosidase positive cells and the levels of senescencemarker p21, and provoked S phasearrestof activated HSC. Remarkably, CRD treatment abolished TGF-β-induced yes-associated protein (YAP) nuclear translocation that acts upstream of glutaminolysis in activated HSC. On the whole, CRD significantly inhibited glutaminolysis of activated-HSC and induced cell senescence through the YAP signaling pathway, consequently alleviating liver fibrosis, which may be a valuable supplement for treating liver fibrosis.

Keywords

Cordycepin; GLS1; Glutaminolysis; Hepatic stellate cell; Liver fibrosis; YAP.

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