Objective: To explore the intervention effect and mechanism of Lentinan (LNT) on liver ferroptosis in mice exposed to sodium arsenite (SA). Methods: C57BL/6 male mice as experimental subjects, The experiment was divided into control group, SA low-dose group, SA high-dose group, and LNT intervention+SA high-dose group. Biochemical methods and Hematoxylin eosin (HE) staining of liver tissue were applied to evaluate hepatic pathological damage; Enzyme linked immunosorbent assay (Elisa) was used to detect the levels of tumor necrosis factorα (TNFα), microtubule associated protein 1 light chain 3B (MAP1LC3B), Interleukin-6 (IL-6), glutathione peroxidase 4 (GPX4), and iron ions (Fe); Immunoblotting (WB) or immunoprecipitation (IP) methods were used to detect the levels of ferritin heavy chain (FTH1), ratio of LC3B to LC3A, or the co-expressions of FTH1 and LC3, or FTH1 and ubiquitin (Ub); Molecular docking software was applied to analyze the interactions between mitochondrial ferritin (FTMT) and LC3A, LC3B, or Ub. Results: Compared with control group, SA exposure group exhibited hepatic pathological damage and the elevated levels of AST, ALT, TNFα, and IL-6, and the elevated ferritinophagy markers LC3B, FTH1, and Fe, while the levels of ferroptosis biomarkers GPX4 decreased (P<0.05); Compared with SA exposure group, LNT intervention showed a significant reduction in hepatic pathological damage, and showed the downregulations of AST, ALT, TNFα, IL-6, LC3B, FTH1, and Fe, while the level of GPX4 upregulated (P<0.05); WB or IP experiment showed that SA exposure induced the upregulated levels of FTH1 and LC3B/A, and the higher co-expressions of FTH1 and LC3B or Ub protein compared to control group, while LNT intervention showed the downregulated levels of FTH1 and LC3B/A, and the decreased co-expressions of FTH1 and LC3B or Ub protein compared to SA exposure group (P<0.05). Molecular docking simulations showed that FTMT binds stably to LC3A, LC3B or Ub by hydrogen bond. Conclusion: Lentinan antagonizes against sodium arsenite exposure mice hepatic injury and ferroptosis, which may be associated with the inhibition or TNFα-ferritinophagy signaling.