GINS4 suppresses ferroptosis by antagonizing p53 acetylation with Snail

Ferroptosis is an iron-dependent oxidative, nonapoptotic form of regulated cell death caused by the destruction of redox homeostasis. Recent studies have uncov-ered complex cellular networks that regulate ferroptosis. GINS4 is a promoter of eukaryotic G(1)/S-cell cycle as a regulator of initiation and elongation of DNA rep-lication, but little is known about its impact on ferroptosis. Here, we found that GINS4 was involved in the regulation of ferroptosis in lung adenocarcinoma (LUAD). CRISPR/Cas9-mediated GINS4 KO facilitated ferroptosis. Interestingly, depletion of GINS4 could effectively induce G(1), G(1)/S, S, and G(2)/M cells to ferroptosis, especially for G(2)/M cells. Mechanistically, GINS4 suppressed p53 stability through activating Snail that antagonized the acetylation of p53, and p53 lysine residue 351 (K351 for human p53) was the key site for GINS4-suppressed p53-mediated ferroptosis. Together, our data demonstrate that GINS4 is a potential oncogene in LUAD that functions to destabilize p53 and then inhibits ferroptosis, providing a potential therapeutic target for LUAD.

Automated summary

This study found that GINS4 is involved in the regulation of ferroptosis in lung adenocarcinoma (LUAD). CRISPR/Cas9-mediated GINS4 knockout promoted ferroptosis, especially in G(2)/M phase cells. The mechanism revealed that GINS4 suppressed p53 stability by activating Snail and inhibiting p53 acetylation, with p53 lysine residue 351 playing a key role in GINS4-suppressed p53-mediated ferroptosis. These findings suggest that GINS4 may be a potential oncogene and a therapeutic target for LUAD.