A polysaccharide from Pueraria lobata ameliorates hepatic fibrosis via gut microbiota-dependent suppression of ferroptosis.

BACKGROUND

Hepatic fibrosis, driven by oxidative stress and subsequent hepatocellular injury, represents a major worldwide health challenge. Pueraria lobata Radix, a traditional Chinese herb, contains polysaccharides with demonstrated hepatoprotective properties, though their mechanisms remain incompletely defined.

PURPOSE: This study aims to characterize the structure of P. lobata polysaccharide (PLP2) and to decipher its protective mechanisms against hepatic fibrosis.

METHODS

PLP2, a homogeneous, water-soluble polysaccharide, was purified from P. lobata and structurally characterized. Subsequently, the hepatoprotective activity of PLP2 was investigated in a CCl₄-induced murine model of hepatic fibrosis.

RESULTS

Structural analysis indicated that PLP2 (Mw = 142.9 kDa) was mainly composed of (1→4)-α-D-Glc and (1→4)-α-D-GalA units, with a minor presence of →4,6)-α-D-Glc-(1→ residues. In a CCl₄-induced murine model of hepatic fibrosis, PLP2 treatment effectively ameliorated liver injury, histopathological damage, and inflammatory responses. Mechanistically, PLP2 treatment restored mitochondrial ultrastructure and hepatic ATP levels, thereby suppressing hepatic ferroptosis through the activation of the Nrf2/HO-1/GPX4 axis. The indispensable role of Nrf2 was further validated using the inhibitor ML385, which abolished PLP2's protection. Notably, the hepatoprotective effects of PLP2 were predominantly dependent on gut microbiota integrity, as direct PLP2 treatment failed to protect hepatocytes in vitro. This role was further confirmed by the abolition of protection with antibiotic treatment and the transfer of benefits via fecal microbiota transplantation.

CONCLUSION

These findings provide evidence that PLP2 exerts its anti-fibrotic effects through the gut microbiota-dependent suppression of ferroptosis via the Nrf2/HO-1/GPX4 axis, providing a solid scientific foundation for the clinical application of P. lobata.