Design, synthesis of a novel ginsenoside derivative and its protection against acetaminophen induced liver injury via suppressing HIF1α-mediated glycolytic metabolism
4 affiliations
- 1College of Pharmacy, Jilin Medical University
- 2Jilin Integrated Traditional Chinese and Western Medicine Hospital of Jilin Province
- 3Jilin Sixth People’s Hospital
- 4Clinical Medical College, Jilin Medical University
Abstract
Background: Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI). Inspired by the synergistic hepatoprotective effects of (20S, 24R)-ocotillol (OC) and lipoic acid (LA), we designed and synthesized OCLA, a novel ginsenoside derivative that has been granted a patent.
Methods: The structure of OCLA was confirmed using HRMS, ¹ H NMR, and ¹³ C NMR. In vitro protective effects against APAP-induced HepG2 cell death were evaluated. In vivo , mice were treated with 32 mg/kg OCLA, followed by assessment of serum ALT/AST levels, hepatic total glutathione (GSH), oxidized glutathione (GSSG), the GSH/GSSG ratio and histopathological liver damage. Additionally, UPLC-MS/MS was utilized to determine the pharmacokinetic parameters of OCLA in mice plasma and liver tissues. Integrated transcriptomic and metabolomic sequencing, along with molecular docking and CETSA experiments, were performed to identify the key pathway and binding targets.
Results: OCLA demonstrated superior protective effects against APAP-induced HepG2 cell death compared to OC in vitro . In vivo , OCLA pretreatment significantly mitigated APAP-induced elevation of serum ALT/AST, restored hepatic GSH/GSSG redox homeostasis, and ameliorated histopathological liver damage. Pharmacokinetic analysis demonstrated prominent hepatic accumulation of OCLA, exhibiting substantially higher AUC and Cmax in liver than in plasma. Integrated omics analysis identified the HIF1α signaling pathway as the key target of OCLA. Molecular docking and CETSA further showed that OCLA directly targeted HIF1α, suppressed its expression, and consequently blocked HIF1α-mediated glycolysis-related genes expression ( GLUT1, HK1, HK2, PFKL, PFKFB3, ENO1 ), inflammatory responses (IL-6, TNF-α) and apoptosis-related proteins expression.
Conclusion: OCLA pretreatment confers protective effects against APAP-induced liver injury primarily by inhibiting HIF1α-associated dysregulation of glycolysis-related molecular signatures and inflammatory responses, showing promising preventive potential for drug-induced liver injury.
Related
- Fisetin Induces Apoptosis and Inhibits Migration of Melanoma Cells by Suppressing Glycolytic Metabolism via PKM2 Inhibition.
- Differential Protection against Acetaminophen-induced Liver and Kidney Injury by N-Acetylcysteine and Fomepizole in Female Mice
- Gene expression, Antioxidant Responses, and metabolomic Profiling Reveal Chlorella vulgaris Mediated Protection against acetaminophen and microplastic Co-toxicity in Oreochromis niloticus
- A Tanshinone IIA Sulfonate Derivative Targets USP21 to Induce SCD1 Degradation, Suppressing NSCLC Metabolism and Enhancing Antitumor Immunity
- Association between early postoperative acetaminophen exposure and acute kidney injury across surgical cohorts: a retrospective analysis of the MIMIC-IV database
BibTeX
@article{han2026design,
title = {{Design, synthesis of a novel ginsenoside derivative and its protection against acetaminophen induced liver injury via suppressing HIF1α-mediated glycolytic metabolism}},
author = {Liu Han and Qiuyue Zhang and Wei Shang and Xiao Wang and Yu Han and Qi Wang and Haiying Ren and Xiangyu Ma and Liancong Gao and Sheng Chang and Xin Sun},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1942215},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1942215/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design, synthesis of a novel ginsenoside derivative and its protection against acetaminophen induced liver injury via suppressing HIF1α-mediated glycolytic metabolism
AU - Liu Han
AU - Qiuyue Zhang
AU - Wei Shang
AU - Xiao Wang
AU - Yu Han
AU - Qi Wang
AU - Haiying Ren
AU - Xiangyu Ma
AU - Liancong Gao
AU - Sheng Chang
AU - Xin Sun
PY - 2026
DA - 2026/10/19
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1942215
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1942215/full
AB - Background: Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI). Inspired by the synergistic hepatoprotective effects of (20S, 24R)-ocotillol (OC) and lipoic acid (LA), we designed and synthesized OCLA, a novel ginsenoside derivative that has been granted a patent. Methods: The structure of OCLA was confirmed using HRMS, ¹ H NMR, and ¹³ C NMR. In vitro protective effects against APAP-induced HepG2 cell death were evaluated. In vivo , mice were treated with 32 mg/kg OCLA, followed by assessment of serum ALT/AST levels, hepatic total glutathione (GSH), oxidized glutathione (GSSG), the GSH/GSSG ratio and histopathological liver damage. Additionally, UPLC-MS/MS was utilized to determine the pharmacokinetic parameters of OCLA in mice plasma and liver tissues. Integrated transcriptomic and metabolomic sequencing, along with molecular docking and CETSA experiments, were performed to identify the key pathway and binding targets. Results: OCLA demonstrated superior protective effects against APAP-induced HepG2 cell death compared to OC in vitro . In vivo , OCLA pretreatment significantly mitigated APAP-induced elevation of serum ALT/AST, restored hepatic GSH/GSSG redox homeostasis, and ameliorated histopathological liver damage. Pharmacokinetic analysis demonstrated prominent hepatic accumulation of OCLA, exhibiting substantially higher AUC and Cmax in liver than in plasma. Integrated omics analysis identified the HIF1α signaling pathway as the key target of OCLA. Molecular docking and CETSA further showed that OCLA directly targeted HIF1α, suppressed its expression, and consequently blocked HIF1α-mediated glycolysis-related genes expression ( GLUT1, HK1, HK2, PFKL, PFKFB3, ENO1 ), inflammatory responses (IL-6, TNF-α) and apoptosis-related proteins expression. Conclusion: OCLA pretreatment confers protective effects against APAP-induced liver injury primarily by inhibiting HIF1α-associated dysregulation of glycolysis-related molecular signatures and inflammatory responses, showing promising preventive potential for drug-induced liver injury.
SN - 1663-9812
ER -