The Metazoan SpoT Homolog 1 promotes ferroptosis by regulating the intracellular redox cycle and iron levels in hepatocellular carcinoma.

[BACKGROUND] Ferroptosis, a form of programmed cell death, is a potential target for cancer therapy. Metazoan SpoT Homolog 1 (MESH1) possesses intracellular NADPH phosphatase activity, which has been linked to ferroptosis. However, the molecular effects on the ferroptosis in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate the relationship between MESH1 expression and the prognosis of patients with HCC, as well as its impact on ferroptosis in HCC cells.

[METHODS] We used resected specimens from patients to assess the relationship between MESH1 expression and prognosis. HCC cell lines were used to evaluate the impact of MESH1 expression on the cell phenotype and ferroptosis through various assays, RNA sequencing, and an animal experiment with xenograft mice model.

[RESULTS] We found that high MESH1 expression correlated with good outcomes. Further investigation demonstrated that MESH1 also exhibits NADPH phosphatase activity in HCC, contributing to increased sensitivity to ferroptosis when the ferroptosis inducer was used. Similar results were observed with other ferroptosis inducers, sorafenib and lenvatinib. Notably, RNA sequencing analysis of cells with MESH1 KD revealed a correlation between intracellular iron homeostasis and MESH1 levels. These results suggested that MESH1 also can affect ferroptosis sensitivity through changing intracellular iron levels. Tumors derived from MESH1 KD cells in xenograft mice showed reduced sensitivity to sorafenib and lenvatinib, further supporting the role of MESH1 ferroptosis regulation.

[CONCLUSION] This study suggests that MESH1 influences intracellular redox and iron regulatory pathways, both of which are linked to cellular processes associated with ferroptosis.