2. Academic Validation
  3. Genistein Ameliorates Rifampicin-Undermined Hepatic Cholesterol Efflux via the CH25H-LXRα-ABCA Pathway

Genistein Ameliorates Rifampicin-Undermined Hepatic Cholesterol Efflux via the CH25H-LXRα-ABCA Pathway

  • J Agric Food Chem. 2025 Dec 29. doi: 10.1021/acs.jafc.5c08641.
Wei Jiang 1 2 3 4,  Ding Zhang 1 2 3,  Jinsheng Shen 1 2 3,  Xionghong Hu 5,  Xueli Jin 1 2 3,  Shelly Tan 6,  Li Zeng 1 2 3,  Hankun Wang 1 2 3,  Shanshan Han 1 2 3,  Jin Chao 1 2 3,  Qiuping Peng 7,  Zhaoyang Liu 1 2 3,  Qing-Ao Xiao 8,  Lin Han 9,  Yiling Huang 1 2,  Xiaochen Zhang 1 2 3,  Bo Yu 9,  Yincheng Zhu 10,  Wei Liu 11,  Xiaofei Huang 1 4,  Xuan Xia 1 2 3 12,  Decheng Wang 1 2 3
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang 443002, China.
  • 2 College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, China.
  • 3 Yichang Key Laboratory of Infection and Inflammation, China Three Gorges University, Yichang 443002, China.
  • 4 College of Medicine and Health Sciences, China Three Gorges University, Yichang 443002, China.
  • 5 Department of Laboratory Medicine, The Third People's Hospital of Yichang, Yichang 443000, China.
  • 6 Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47906, United States of America.
  • 7 Department of Gastroenterology and Hepatology, The Third People's Hospital of Yichang, Yichang 443000, China.
  • 8 Department of Interventional Radiology, Yichang Central People's Hospital, the First College of Clinical Medical Science, China Three Gorges University, Yichang 443003, China.
  • 9 Department of Pathology, Yichang Center People's Hospital, the First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, China.
  • 10 Yichang Yiling District Animal Disease Prevention and Control Center, Yichang 443100, China.
  • 11 Institute of Digestive Disease, The First College of Clinical Medical Science, Yichang Central People's Hospital, China Three Gorges University, Yichang 443003, China.
  • 12 Department of Physiology and Pathophysiology, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, China.
PMID: 41459645 DOI: 10.1021/acs.jafc.5c08641
Abstract

Rifampicin (RFP) is a well-known first-line antitubercular drug recommended by the World Health Organization. However, RFP-induced hepatotoxicity makes it impractical for use in long-term antitubercular therapy, and its mechanism is still incompletely understood. This study decrypts the mechanism of aberrant Cholesterol metabolism in RFP-mediated liver injury and explores the protective effects of genistein (GEN), an isoflavone isolated from the dyer's broom plant (Genista tinctoria), when used in conjunction with RFP. RFP significantly promoted the formation of lipid droplets, increasing Cholesterol deposition in liver by reducing Cholesterol 25-hydroxylase (CH25H) and its downstream effector LXRα-ABCA to decrease Cholesterol efflux. GEN upregulated CH25H and ultimately relieved RFP-induced liver injury; furthermore, replacing endogenous 25-hydroxycholesterol (25HC) both in vivo and in vitro accordingly rescued the hepatotoxicity induced by RFP. Finally, molecular docking and cellular thermal shift assay (CETSA) showed that RFP could bind to CH25H and impair its stability, an interaction that could be reversed by GEN. Thus, RFP restrains Cholesterol efflux by reducing the CH25H-LXRα-ABCA axis to trigger steatosis, while GEN restores this pathway by upregulating CH25H, facilitating Cholesterol efflux and mitigating RFP-induced liver injury.

Keywords

ABCA; cholesterol 25-hydroxylase (CH25H); cholesterol efflux; drug-induced liver injury (DILI); genistein; rifampicin (RFP).

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