Mannose attenuates CCl₄-induced liver fibrosis by reducing oxidative stress through AMPK-dependent NRF2 signaling

Mannose, a naturally occurring hexose, has been implicated in the regulation of metabolism and inflammation. Although emerging evidence suggests its therapeutic potential in liver diseases, the mechanisms by which mannose modulates liver fibrosis, particularly in relation to oxidative stress, remain poorly defined. This study aimed to investigate the protective effects of mannose in liver fibrosis and elucidate the underlying mechanisms. A CCl₄-induced mouse model of liver fibrosis was established with mannose administered in drinking water. Transcriptomic analysis was performed to explore potential mechanisms. Hepatic oxidative stress, inflammatory responses, and nuclear factor erythroid 2-related factor 2 (NRF2) signaling were evaluated. NRF2 function was assessed using the inhibitor ML385 in vivo and in primary mouse hepatocytes (PMH). The involvement of AMP-activated protein kinase (AMPK) was further examined in PMH using Compound C. The results showed that mannose markedly attenuated liver fibrosis and injury, accompanied by reduced oxidative stress and decreased inflammatory and pro-fibrotic mediators. Transcriptomic and biochemical analyses indicated enhanced NRF2 signaling in mannose-treated livers. ML385 largely abolished the protective effects of mannose in vivo and in vitro, supporting a functional role of NRF2 signaling. Mechanistically, mannose increased AMPK phosphorylation, whereas Compound C suppressed NRF2 signaling and reversed its antioxidant effects. Moreover, conditioned medium from mannose-treated PMH attenuated hepatic stellate cell (HSC) activation, suggesting that mannose primarily protects hepatocytes and indirectly limits HSC activation. Mannose alleviates liver fibrosis by reducing oxidative stress and inflammation, at least in part through an AMPK-dependent NRF2 signaling pathway. These findings provide mechanistic insight into the anti-fibrotic effects of mannose and support further investigation of its potential as a nutritional intervention for liver disease.