Limonin mitigates hepatic senescence and fibrosis in MASH mice by targeting STAT3 to inhibit Galectin-3/mTORC1 signaling
- Phytomedicine. 2026 Jul:156:158244. doi: 10.1016/j.phymed.2026.158244.
- 1. Department of Pharmacy, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China.
- 2. Zhejiang Chinese Medical University Affiliated Four-provinces Marginal Hospital of Traditional Chinese Medicine, Quzhou Hospital of Traditional Chinese Medicine, Quzhou 324000, China.
- 3. Department of Infectious Diseases, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China. Electronic address: [email protected].
- 4. Department of Pharmacy, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China. Electronic address: [email protected].
Background: Despite existing reports on the hepatoprotective effects of limonin (Lim), its specific impact on hepatic fibrosis and cellular senescence in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. The precise molecular mechanisms and direct targets underpinning its pharmacological activity are also poorly defined.
Purpose: This research aimed to investigate the therapeutic potential of Lim against MASH-related hepatic fibrosis and senescence, and to delineate the underlying molecular pathways.
Methods: A murine MASH model was generated by feeding a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). To elucidate the mechanism of action of Lim, an integrated strategy was adopted, comprising AAV8-mediated gene manipulation, RNA Sequencing (RNA-seq), and pharmacological interventions with agonists or inhibitors. The direct protein targets of Lim were identified using human proteome microarrays and validated through molecular docking, pull-down assays, and site-directed mutagenesis.
Results: Our findings indicate that Lim effectively alleviates hepatic fibrosis and senescence in MASH mice, while suppressing Galectin-3 expression and mechanistic target of rapamycin complex 1 (mTORC1) activation. Notably, targeted knockdown of Galectin-3 in the liver hindered aging-related changes in MASH mice, with mTORC1 functioning as a downstream effector. Further results revealed that mTORC1 acts as a key mediator of Lim's protective effects against hepatic fibrosis and senescence in MASH mice. Mechanistically, Lim binds to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3 (STAT3), inhibiting its activity and leading to reduced Galectin-3 expression and mTORC1 activation. Moreover, the application of STAT3 Inhibitor has been shown to alleviate hepatic fibrosis and senescence in MASH mice, further corroborating the suppression of Galectin-3 and mTORC1 activity.
Conclusion: In conclusion, our study provides compelling evidence for the efficacy of Lim in ameliorating hepatic senescence and fibrosis in MASH mice, elucidating the involvement of the STAT3/Galectin-3/mTORC1 signaling in these processes.