Potentilla anserina L. (PA) belongs to the Rosaceae family, is a common edible plant in the Qinghai-Tibet Plateau areas of China. This study elucidates the mechanism upon which crude polysaccharide of PA (PAP) on fat accumulation in HepG2 cells stimulated by oleic acid (OA) and high fat high sugar induced mice. The result revealed that PAP inhibited lipid accumulation in obese mice and ameliorated the degree of damage in OA-induced HepG2 cells. Specifically, compared to the control group, the TG and TC levels were decreased in cells and mice serum, the aspartate transaminase and alamine aminotransferase contents were declined in liver of obese mice by PAP treatment. The expressions of adipogenic genes of SREBP-1c, C/EBPα, PPARγ, and FAS were inhibited after PAP treatment. Moreover, PAP increased the mRNA levels of CPT-1 and PPARα, which were involved in fatty acid oxidation. The present results indicated the PAP could alleviate the damage of liver associated with obesity and PAP treatment might provide a dietary therapeutic option for the treatment of hyperlipidemia.

Alcoholic liver injury (ALD) is a serious liver disease resulting from prolonged and excessive alcohol consumption, with significant morbidity and mortality and closely relate to iron accumulation and ferroptosis. Ferritinophagy is the process of autophagic degradation of ferritin and results in labile iron accumulation and ferroptosis. However, whether ferritinophagy involves in alcohol-induced liver injury and ferroptosis remains unexplored. Here, we demonstrated the involvement of ferroptosis in alcohol-induced liver injury by modulating nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Utilizing both in vivo and in vitro models, we observed activation of autophagy and ferroptosis following alcohol administration. Intriguingly, we found that alcohol-induced ferroptosis is autophagy-dependent, because autophagy inhibitor 3-MA (30 mg/kg bw. in vivo, 1 mM in vitro, respectively) profoundly mitigated alcohol-induced ferroptosis. We further demonstrated that alcohol-induced ferritinophagy was derived by iron overload, by showing that iron chelator DFO (100 mg/kg bw. in vivo, 10 μM in vitro, respectively) can abolish alcohol-induced ferritinophagy and ferroptosis. Moreover, we observed an upregulation of NCOA4 expression, and knockdown of NCOA4 significantly reversed alcohol-induced disturbances in iron metabolism and subsequently blocking ferroptosis. Our findings suggest a connection between ferritinophagy and alcohol-induced ferroptosis in mouse liver and HepG2 cells, highlighting NCOA4-mediated ferritinophagy as a novel mechanism of alcohol-induced liver injury. This study enhances our understanding of the molecular mechanisms underlying alcohol-induced liver injury, and targeting ferritinophagy may provide new strategies for preventing or treating ALD.