Jessalyn M. Ubellacker课题组取得一项新突破。他们的最新研究揭示了淋巴结环境驱动FSP1在转移性黑色素瘤中的靶向性。相关论文于2025年11月5日发表于国际顶尖学术期刊《自然》杂志上。

通过选择淋巴结转移的转移性黑色素瘤模型，研究组发现淋巴结源性转移细胞的谷氨酸-半胱氨酸连接酶（GCLC）表达明显降低，谷胱甘肽（GSH）水平相对于亲代细胞降低。这种代谢转变发生在缺氧淋巴生态位内。在类似的低氧条件下，GPX4经历泛素化和蛋白酶体降解。作为反应，淋巴结转移细胞增加了对铁下垂抑制蛋白1 （FSP1）的依赖，该蛋白定位于核周溶酶体。这些发现表明，对GPX4轴依赖性的降低使黑色素瘤细胞转向对FSP1的依赖性。值得注意的是，使用选择性FSP1抑制剂（viFSP1和FSEN1）进行瘤内单药治疗可以有效抑制淋巴结中的黑色素瘤生长，但在皮下肿瘤中却没有，这强调了对FSP1的微环境特异性依赖。因此，针对淋巴结中的FSP1具有阻断黑色素瘤进展的强大潜力。

据介绍，铁下垂已成为消除治疗耐药和转移性癌症的可行靶点。然而，哪种铁下垂监测系统可能为利用癌症中的氧化还原适应不良提供治疗窗口仍不清楚。在黑色素瘤中，谷胱甘肽过氧化物酶4 （GPX4）在血色素转移过程中阻碍铁凋亡，但在淋巴转移过程中是必不可少的。

附：英文原文

Title: Lymph node environment drives FSP1 targetability in metastasizing melanoma

Author: Palma, Mario, Chaufan, Milena, Breuer, Cort B., Mller, Sebastian, Sabatier, Marie, Fraser, Cameron S., Szylo, Krystina J., Yavari, Mahsa, Carmona, Alanis, Kaur, Mayher, Melo, Luiza Martins Nascentes, Cansiz, Feyza, Monge-Lorenzo, June, Flores, Midori, Mishima, Eikan, Nakamura, Toshitaka, Proneth, Bettina, Labrado, Marcos, Liang, Yanshan, Cayting, Nicole, Zheng, Lan, Caeque, Tatiana, Colombeau, Ludovic, Wahida, Adam, Friedmann Angeli, Jos Pedro, Tasdogan, Alpaslan, Hui, Sheng, Rodriguez, Raphal, Conrad, Marcus, Reticker-Flynn, Nathan E., Ubellacker, Jessalyn M.

Issue&Volume: 2025-11-05

Abstract: Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers1. However, which ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in cancer remains unclear. In melanoma, glutathione peroxidase 4 (GPX4) impedes ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis2. Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate–cysteine ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts. This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation. In response, lymph node metastatic cells acquire increased reliance on ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes. These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency. Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1. Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression.

DOI: 10.1038/s41586-025-09709-1

Source: https://www.nature.com/articles/s41586-025-09709-1