GINS4通过Snail拮抗p53乙酰化抑制肺腺癌铁死亡的机制研究

肺腺癌是肺癌最常见的病理类型，易侵袭转移。铁死亡是一种新型调节性细胞死亡模式。.具有EMT/侵袭特性的肿瘤对铁死亡敏感，然而其机制仍不清楚。我们前期工作表明，DNA复制分子GINS4在肺腺癌组织异常高表达，并促进肺腺癌细胞增殖和转移。基于此，本项目拟探讨GINS4通过上调EMT关键分子Snail，拮抗野生型p53乙酰化并促进其降解，从而抑制野生型p53对铁死亡的促进作用，促使肺腺癌发生发展。抑制GINS4的表达可增加G2/M期细胞对铁死亡的敏感性，从而遏制肺腺癌的侵袭与转移。.本课题将深入研究GINS4在肺腺癌中抑制铁死亡的生物学意义、GINS4通过Snail拮抗p53乙酰化的分子机制，以及探讨GINS4/Snail/p53这一通路在肺腺癌铁死亡中的重要作用，最终揭示GINS4在肺腺癌发生发展中的功能，有望为p53野生型和转移型肺腺癌的治疗提供理论依据。

Lung adenocarcinoma is the most common pathological type of lung cancer, which is prone to metastasis, and ferroptosis is a new type of programmed cell death. .Recently, it is reported that tumors with EMT and invasive characteristics are sensitive to ferroptosis. However, the mechanism of this phenomenon is still not clear. Our previous study showed that the GINS complex subunit 4 (GINS4), which is essential for DNA replication and cell cycle in eukaryotes, was highly expressed and could promote the proliferation and metastasis of lung adenocarcinoma cells. Based on this, our project intends to explore that GINS4 may up-regulate EMT key player Snail, thus inhibit acetylation of wild-type p53, promote its degradation, impair its promotion on ferroptosis, and ultimately promote survival and proliferation of lung adenocarcinoma cells. Besides，we found that inhibiting GINS4 expression in lung adenocarcinoma cells could promote sensitivity of G2/M phase cells to ferroptosis, and suppress invasion and metastasis of lung adenocarcinoma cells. .Our project will deeply research the biological significance of GINS4 suppressed ferroptosis in lung adenocarcinoma, the molecular mechanism of GINS4 antagonizing p53 acetylation through Snail, explore the important role of GINS4/snail/p53 pathway in ferroptosis of lung adenocarcinoma, and finally reveal the function of GINS4 in the occurrence and development of lung adenocarcinoma. It is expected to provide a theoretical basis for the treatment of wild-type p53 expressed and metastatic lung adenocarcinoma.