Chiisanoside from the Leaves of Acanthopanax sessiliflorus Can Resist Cisplatin-Induced Ototoxicity by Maintaining Cytoskeletal Homeostasis and Inhibiting Ferroptosis

  • J Agric Food Chem. 2024 Nov 20;72(46):25720-25742. doi: 10.1021/acs.jafc.4c07994.
Hongbo Teng  1  2 ,  Xialin Sun  2  3 ,  Roberts Eglitis  4 ,  Xv Wang  1  2 ,  Wenxin Zhang  1  2 ,  Haijing Wang  1  2 ,  Shurong Qu  1  2 ,  Zhengxuan Yu  1 ,  Shuangli Liu  1  2 ,  Yan Zhao  1  2
Affiliations
  • 1. College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China.
  • 2. International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun, Jilin Province 130118, China.
  • 3. College of Pharmacy, Jilin Medical University, Jilin, Jilin Province 132013, China.
  • 4. Institute of Solid State Physics, University of Latvia, Riga LV-1067, Latvia.
PMID: 39505327 DOI: 10.1021/acs.jafc.4c07994
Abstract

Ototoxicity is a common side effect of cisplatin Cancer treatment, potentially leading to hearing loss. This study demonstrated the significant protective activity of Acanthopanax sessiliflorus (A. sessiliflorus) leaves against cisplatin-induced ototoxicity (CIO), investigated the active compounds, and elucidated their mechanisms in countering CIO. UPLC-Q/TOF-MS analysis identified 79 compounds. Network pharmacology and activity screening determined that chiisanoside (CSS) plays a crucial role in combating CIO. Transcriptomics combined with network pharmacology analysis and experiments revealed that CSS activates the Dock1/PIP5K1A pathway to suppress the actin-severing protein gelsolin, protecting hair cells from cisplatin-induced Cytoskeleton damage. CSS also activates the SLC7A11/GPX4 pathway via TGFBR2, reducing lipid peroxidation and intracellular iron accumulation to suppress cisplatin-induced Ferroptosis. This study discovers that the major component CSS in A. sessiliflorus leaves reverses CIO by regulating Actin homeostasis via Dock1 and inhibiting Ferroptosis through TGFBR2, providing a theoretical basis for expanding CIO treatment targets and related drug development.

Keywords
RNA sequencing; chiisanoside (CSS); cisplatin-induced ototoxicity (CIO); cytoskeletal homeostasis; ferroptosis; network pharmacology.
Products