Identification of flupirtine as a candidate against liver fibrosis in mice: Preserving mitochondria quality by suppressing calpain 1/complex I/mtROS axis via targeting asparagine synthase
- 1Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570100, China
- 2Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- 3School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering and Technology Research Center, Guangdong Pharmaceutical University, Zhongshan 528458, China
Abstract
Liver fibrosis is a pressing clinical challenge, poses a huge threat to human health. However, there is no approved therapeutic medication to treat this devastating disease. Using a drug repositioning or drug rescue (DDDR) strategy, we identified the anti-analgesic agent flupirtine as a potential anti-liver fibrosis candidate through cell-based high-throughput screening of the FDA-approved drug library. Treatment with flupirtine reversed TGF-β1-induced fibrogenesis and ameliorated liver fibrosis in CCl4 or DDC diet-treated fibrotic mice. Asparagine synthase (ASNS) was identified as the direct target of flupirtine. Flupirtine interacted with the residues Asp 401 and Arg 404 of ASNS, thereby inhibiting its enzymatic activity. Importantly, ASNS levels were increased in activated hepatic stellate cells (acHSCs) and in the livers of fibrotic mice and humans, and are positively correlated with the severity of liver fibrosis. Mechanistically, inhibition or deletion of ASNS to increase l-aspartate levels reversed TGF-β1-induced Ca2+ overload in mitochondria, leading to suppression of calpain 1/complex I/mitochondrial reactive oxygen species (mtROS) axis, thereby improving mitochondrial quality and enhancing mitochondrial oxidation, ultimately counteracting liver fibrosis. Our study identified ASNS as a potential therapeutic target for treating liver fibrosis, flupirtine counteracted liver fibrosis in mice by suppressing ASNS in acHSCs, thereby blocking mitochondrial Ca2+/calpain 1/complex I/mtROS axis.
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BibTeX
@article{rao2026identification,
title = {{Identification of flupirtine as a candidate against liver fibrosis in mice: Preserving mitochondria quality by suppressing calpain 1/complex I/mtROS axis via targeting asparagine synthase}},
author = {Yong Rao and Rui Su and Huiling Fu and Jin Liu and Wenjie Cao and Zichao Yang and Chen Zhang and Xiaoxuan Su and Feifei Liu and Zhongping Jiang and Congjun Xu and Wandi Xiong and Haibin Luo and Ling Huang},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = aug,
doi = {10.1016/j.apsb.2026.08.017},
url = {https://europepmc.org/article/PMC/PMC13729717},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Identification of flupirtine as a candidate against liver fibrosis in mice: Preserving mitochondria quality by suppressing calpain 1/complex I/mtROS axis via targeting asparagine synthase
AU - Yong Rao
AU - Rui Su
AU - Huiling Fu
AU - Jin Liu
AU - Wenjie Cao
AU - Zichao Yang
AU - Chen Zhang
AU - Xiaoxuan Su
AU - Feifei Liu
AU - Zhongping Jiang
AU - Congjun Xu
AU - Wandi Xiong
AU - Haibin Luo
AU - Ling Huang
PY - 2026
DA - 2026/08/21
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.08.017
UR - https://europepmc.org/article/PMC/PMC13729717
AB - Liver fibrosis is a pressing clinical challenge, poses a huge threat to human health. However, there is no approved therapeutic medication to treat this devastating disease. Using a drug repositioning or drug rescue (DDDR) strategy, we identified the anti-analgesic agent flupirtine as a potential anti-liver fibrosis candidate through cell-based high-throughput screening of the FDA-approved drug library. Treatment with flupirtine reversed TGF-β1-induced fibrogenesis and ameliorated liver fibrosis in CCl4 or DDC diet-treated fibrotic mice. Asparagine synthase (ASNS) was identified as the direct target of flupirtine. Flupirtine interacted with the residues Asp 401 and Arg 404 of ASNS, thereby inhibiting its enzymatic activity. Importantly, ASNS levels were increased in activated hepatic stellate cells (acHSCs) and in the livers of fibrotic mice and humans, and are positively correlated with the severity of liver fibrosis. Mechanistically, inhibition or deletion of ASNS to increase l-aspartate levels reversed TGF-β1-induced Ca2+ overload in mitochondria, leading to suppression of calpain 1/complex I/mitochondrial reactive oxygen species (mtROS) axis, thereby improving mitochondrial quality and enhancing mitochondrial oxidation, ultimately counteracting liver fibrosis. Our study identified ASNS as a potential therapeutic target for treating liver fibrosis, flupirtine counteracted liver fibrosis in mice by suppressing ASNS in acHSCs, thereby blocking mitochondrial Ca2+/calpain 1/complex I/mtROS axis.
SN - 2211-3835
SN - 2211-3843
ER -