Saikosaponin B1 alleviates hepatic fibrosis by targeting the LDHA-MCT1/4 axis to inhibit lactate-driven profibrogenic signaling.

Abstract

<p>Liver fibrosis, a common consequence of chronic liver diseases, currently lacks effective pharmacological interventions. Saikosaponin B1 (S-B1), a bioactive triterpenoid saponin isolated from Bupleurum chinense, has been shown to exhibit anti-inflammatory and hepatoprotective activities. This study aimed to evaluate the therapeutic potential of S-B1 in carbon tetrachloride (CCl4)-induced hepatic fibrosis and to elucidate its underlying mechanisms. A mouse model of liver fibrosis was established through sequential administration of diethylnitrosamine (DEN) and CCl4, followed by 2&nbsp;weeks of S-B1 treatment. Our results demonstrate that S-B1 significantly ameliorates liver injury, as evidenced by reduced serum ALT and AST levels, improved oxidative stress parameters, and restoration of hepatic histology with attenuated collagen deposition. Moreover, S-B1 downregulates the expression of key fibrogenic genes (Col1a1, Col4a4, TGF-β1, TIMP1), suppresses hepatic stellate cell (HSCs) activation, and reduces inflammatory cell infiltration and cytokine production. In vitro studies using TGF-β1-stimulated LX-2 cells confirm that S-B1 directly inhibits HSC activation, proliferation, and pro-inflammatory responses. Mechanistically, we identify a novel pathway mediating S-B1's anti-fibrotic effects: direct targeting of lactate dehydrogenase A (LDHA) to inhibit lactate production, coupled with concurrent downregulation of the lactate transporters monocarboxylate transporters 1 and monocarboxylate transporters 4. Genetic validation confirms LDHA as an essential target, as LDHA knockdown abrogates S-B1's anti-fibrotic efficacy. In conclusion, S-B1 effectively alleviates hepatic fibrosis by directly targeting HSCs and disrupting a central lactate-driven profibrogenic axis, highlighting its promise as a therapeutic candidate for liver fibrosis.</p>