BACKGROUND & AIMS:Alcohol-related liver disease (ALD) remains a global public health challenge, highlighting the urgent need to uncover novel pathophysiological mechanisms and therapeutic targets. Spermidine, a natural polyamine abundant in dietary plant sources and present in all eukaryotic cells, exhibits versatile biological activities, yet its role in ALD development remains unclear. This study aimed to investigate the changes of spermidine metabolism and evaluate the hepatoprotective potential of spermidine in ALD.
APPROACH & RESULTS:The effects of ethanol on hepatic spermidine homeostasis and the hepatoprotective effects of spermidine were examined in clinical sample analysis, ethanol-fed mouse models, and in vitro systems (AML12 hepatocytes and Caco-2 monolayers). In this study, we provided the first comprehensive evidence from clinical samples, animal models, and cell culture systems demonstrating that ethanol consumption significantly reduced spermidine levels. Ethanol feeding induced an increase in serum aminotransferase activities, liver steatosis, oxidative stress, iron accumulation, and hepatocyte ferroptosis, which were significantly ameliorated by exogenous spermidine supplementation and exacerbated by the spermidine synthesis inhibitor DFMO. Mechanistically, spermidine inhibited iron uptake, prevented ferritin heavy chain (FTH) degradation likely by suppressing ferritinophagy, promoted iron export in hepatocytes, and reduced intestinal iron absorption. Notably, these protective effects were abolished in both global and hepatocyte-specific Nrf2-knockout mice, indicating dependence on NRF2 signaling.
CONCLUSIONS:These results identify ethanol-induced spermidine reduction as a previously unrecognized molecular event in the pathogenesis of ALD and highlight dietary spermidine supplementation as a promising strategy to counteract ethanol-driven iron dysregulation and hepatocyte ferroptosis.