靶向FSP1触发肺癌铁死亡，这一成果由纽约大学格罗斯曼医学院Thales Papagiannakopoulos小组经过不懈努力而取得。相关论文发表在2025年11月5日出版的《自然》杂志上。

课题组人员对肺腺癌的基因工程motheme模型进行了两种关键的铁死亡抑制因子GPX4和铁死亡抑制蛋白1 (FSP1)的肿瘤特异性功能丧失研究，并观察到脂质过氧化和铁死亡抑制肿瘤发生的增加，这表明肺肿瘤对铁死亡高度敏感。

此外，在多个临床前模型中，该团队发现FSP1在体内对铁下沉有保护作用，但在体外没有，这强调了在生理条件下缓冲脂质过氧化的高度需要。脂质组学分析显示，FSP1敲除肿瘤具有脂质过氧化物的积累，通过遗传、饮食或药理学方法抑制铁死亡有效地恢复了FSP1敲除肿瘤在体内的生长。与GPX4不同，FSP1（也称为AIFM2）的表达是肺腺癌患者疾病进展和较差生存的预后因素，突出了其作为可行治疗靶点的潜力。为此，该研究团队证明了FSP1的药理学抑制在临床前肺癌模型中具有显著的治疗效果。他们的研究强调了体内抑制铁死亡的重要性，并为FSP1抑制作为肺癌患者的治疗策略铺平了道路。

研究人员表示，新出现的证据表明，癌细胞易发生铁死亡，这是一种由不受控制的脂质过氧化引发的细胞死亡形式。尽管人们普遍热衷于利用铁死亡作为一种新的抗癌策略，但铁死亡是否是肿瘤发生的障碍，是否可以用于治疗仍然未知。

附：英文原文

Title: Targeting FSP1 triggers ferroptosis in lung cancer

Author: Wu, Katherine, Vaughan, Alec J., Bossowski, Jozef P., Hao, Yuan, Ziogou, Aikaterini, Kim, Seon Min, Kim, Tae Ha, Nakamura, Mari N., Pillai, Ray, Mancini, Mariana, Rajalingam, Sahith, Han, Mingqi, Nakamura, Toshitaka, Wang, Lidong, Chung, Suckwoo, Simeone, Diane, Shackelford, David, Kang, Yun Pyo, Conrad, Marcus, Papagiannakopoulos, Thales

Issue&Volume: 2025-11-05

Abstract: Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation1,2,3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and can be leveraged therapeutically remains unknown4,5. Here, using genetically engineered mouse models of lung adenocarcinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppressors, GPX46,7 and ferroptosis suppressor protein 1 (FSP1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumours are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout tumours had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary or pharmacological approaches effectively restored the growth of Fsp1-knockout tumours in vivo. Unlike GPX4, expression of FSP1 (also known as AIFM2) was prognostic for disease progression and poorer survival in patients with lung adenocarcinoma, highlighting its potential as a viable therapeutic target. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy for patients with lung cancer.

DOI: 10.1038/s41586-025-09710-8

Source: https://www.nature.com/articles/s41586-025-09710-8