Objective To explore the effect and mechanism of lentinan (LNT)on hepatic tissue ferroptosis in mice exposed to sodium arsenite (SA). Methods C57BL/6N male mice were exposed to SA low-dose, SA highdose, and LNT intervention combined with SA high-dose, then, hematoxylin and eosin(HE)staining was applied to assess pathological liver tissue damage; Enzyme-linked immunosorbent and Western blot were used to detect the content or expression of tumor necrosis factor α (TNFα), interleukin-6 (IL-6), ferritinophagy or ferroptosis biomarkers. Results Compared with the control group, SA exposure induced the elevated levels of TNFα, IL-6, ferritinophagy biomarker ferritin heavy chain 1(FTH1)and microtubule-associated protein 1 light chain 3B (MAP1LC3B)in mice liver tissue, while levels the ferroptosis biomarker GPX4 decreased(P<0.05). Compared with SA high-dose groups, LNT intervention showed the reduced pathological liver damage and the downregulated levels of TNFα, IL-6, FTH1, and MAP1LC3B, while the level of GPX4 upregulated(P<0.05). Western blot experiment showed that LNT intervention antagonized the upregulated levels of FTH1, and autophagy biomarker LC3B/A, and antagonized the increased co-expressions of FTH1 with LC3B or Ub protein in SA high-dose group(P<0.05). Conclusions LNT antagonizes SA-exposed hepatic pathological injury and ferroptosis in mice, possibly associated with inhibition of TNFα-ferritinophagy signaling.