Work

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

Year: 2026

Type: article

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- β 1-induced fibrogenesis and ameliorated liver fibrosis in CCl 4 or DDC diet-treated fibrotic mice. Asparagine synthase (ASNS) was identified as the direct target of flupirtine. Flupirtine interacted with the residues Asp401 and Arg404 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- β 1-induced Ca 2+ 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 Ca 2+ /calpain 1/complex I/mtROS axis.

Source: Acta Pharmaceutica Sinica B

DOI: 10.1016/j.apsb.2026.08.017