Ellagic acid alleviates iron overload-induced liver damage by mitigating ferroptosis through modulation of the TGFβ/Smad signaling pathway

• Published in: Food research international Vol. 214; p. 116590
• Main Authors: Fu, Hangjie, Li, Wenxia, Cheng, Qimei, Weng, Zhiwei, Huang, Zhiguang, Zhu, Lijian, Ding, Tao, Ding, Bin
• Format: Journal Article
• Language: English
• Published: Canada Elsevier Ltd 01.08.2025
• Subjects: Animals; Cell Line; Disease Models, Animal; Ellagic acid; Ellagic Acid - pharmacology; Ferric Compounds; Ferroptosis; Ferroptosis - drug effects; Iron - metabolism; iron overload; Iron Overload - complications; Iron Overload - drug therapy; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Oxidative Stress - drug effects; Quaternary Ammonium Compounds; Signal Transduction - drug effects; Smad Proteins - metabolism; TGFβ signaling; Transforming Growth Factor beta - metabolism; SDs; FPN; Liver; Ferroptosis; ALT; TGFBR1/2; TRF; HO-1; MDA; PTGS2; TGFβ signaling; PDB; CETSA; DEGs; 4HNE; RNA-seq; ANOVA; FDR; Ellagic acid; KEGG; p-Smad; qPCR; TBI; EA; GSH; iron overload; NQO1; AST; GPX4; H&E; qRT-PCR; GO; FAC; GST; SOD; EAH; PVDF; ECM; GPx; PUFA-ePLs; EAL; TG; TFR1; CAT; ROS; TGFβ
• ISSN: 0963-9969; 1873-7145; 1873-7145
• DOI: 10.1016/j.foodres.2025.116590

Ellagic acid (EA), a naturally occurring polyphenolic compound abundant in fruits and nuts, has demonstrated promising therapeutic potential in liver disease management. Iron overload, a pathological condition associated with severe hepatic damage, was the focus of this investigation. This study aimed to elucidate the hepatoprotective effects of EA against iron overload-induced liver injury and uncover the underlying molecular mechanisms. Using both a mouse model of iron overload induced by iron dextran and cell model of iron overload induced by ferric ammonium citrate (FAC), we systematically evaluated the biological effects of EA. Our findings revealed that EA significantly attenuated iron overload-induced hepatic injury and fibrosis. Mechanistically, EA not only ameliorated dysregulated iron metabolism and oxidative stress but also suppressed peroxisomal lipid biosynthesis and ferroptosis in the livers of mice with iron overload. Parallel in vitro experiments confirmed the capacity of EA to inhibit FAC-triggered ferroptosis in AML12 cells. Transcriptomic profiling identified ferroptosis-related pathways as key targets of EA intervention. Notably, functional enrichment analysis of the RNA sequencing data highlighted the TGFβ/Smad signaling pathway as the predominant regulatory axis modulated by EA. Importantly, exogenous TGFβ supplementation abolished the antiferroptotic effects of EA, further confirming TGFβ/Smad signaling as the central mechanistic pathway through which EA exerts its protective function. Collectively, our results establish EA as a novel regulator of the TGFβ/Smad axis, effectively mitigating iron overload-driven ferroptosis and subsequent hepatic injury and thereby offering a potential therapeutic strategy for iron-related hepatopathies. [Display omitted] •1.Ellagic acid (EA) effectively alleviates liver injury caused by iron overload.•2.EA ameliorates liver iron metabolism disorders induced by iron overload.•3.EA is a potential ferroptosis inhibitor.•4.EA regulates the TGFβ/Smad signaling pathway to inhibit ferroptosis.