Ferroptosis: A Controlled Form of Cell Death
Ferroptosis is a form of cell death driven by excessive lipid oxidation in cell membranes. When this occurs, the cell’s structural integrity collapses, leading to death. Cancer cells rely heavily on antioxidant proteins like FSP1 to prevent ferroptosis and sustain their uncontrolled growth. By blocking this defense mechanism, researchers hope to reactivate ferroptosis and selectively kill cancer cells.
FSP1 Dependency in Metastatic Melanoma
“Our study shows that melanoma cells in lymph nodes become dependent on FSP1 to survive, and that it is possible to decrease melanoma cell survival in lymph nodes with novel FSP1 inhibitors,” said corresponding author Jessalyn Ubellacker, assistant professor of molecular metabolism at the Harvard T.H. Chan School of Public Health and leading author of the Palma et al. study. “These findings lay the foundation for potential new therapeutic strategies aimed at slowing cancer progression by targeting ferroptosis defense mechanisms.”
Traditionally, most research on ferroptosis resistance has been performed in vitro – in cells and organoids grown in culture dishes. In contrast, the study took a contextual, in vivo approach, asking how the tumor microenvironment influences ferroptosis protection mechanisms. The researchers investigated melanoma cells that had metastasized to lymph nodes, using mouse models of melanoma tumors to test the efficacy of novel FSP1 inhibitors directly within living tissues.
Targeting FSP1 Weakens Cancer’s Defenses
The study by Palma et al. further found that inside lymph nodes, FSP1 acts as a key line of defense against ferroptotic cell death. When the researchers delivered FSP1 inhibitors to the tumors, the tumors’ growth was sharply reduced. In comparison, they tested this same drug on melanoma in vitro and saw little impact on cancer cell death, underscoring the importance of studying cancer in its true physiological environment.
Complementary Findings in Lung Adenocarcinoma
In the same issue of Nature, a complementary study led by the Papagiannakopoulus Laboratory at New York University revealed that inhibiting FSP1 in lung adenocarcinoma (LUAD) cells triggers ferroptosis and reduces tumor growth by up to 80 percent in mice.
Lung adenocarcinoma, the most common lung cancer in nonsmokers, accounts for approximately 40 percent of lung cancer cases worldwide and remains a leading cause of cancer death.
The study by Wu et al. revealed that genetically deleting the Fsp1 gene in lung cancer led to increased cancer cell death and significantly smaller tumors. Treatment of mice with a novel small molecule FSP1 inhibitor, icFSP1, yielded comparable effects and improved the overall survival of tumor-bearing mice.
FSP1 as a Promising and Selective Target
The research team found that FSP1 plays an equally important role in suppressing ferroptosis in lung cancer cells like glutathione peroxidase 4 (GPX4), the prime defense system against ferroptosis. Elevated FSP1 levels were also correlated with poorer survival in human LUAD patients, making it a promising target for future cancer therapies with likely fewer side effects than GPX4 inhibition.
Together, the studies led by Ubellacker and Papagiannakopoulos, strengthen the case for FSP1 as a drug target across multiple cancer types.
“For the first time, these studies identify FSP1 as a druggable target in both tumor metastasis and lung adenocarcinoma,” said Marcus Conrad. “It is a remarkable finding that inhibiting FSP1 alone can suppress tumor growth of lung adenocarcinoma and metastasis – something that could not have been predicted from cell culture experiments.”
Good to Know
Ferroptosis was first coined in 2012. However, even before its official naming, Marcus Conrad and his team at the Institute of Metabolism and Cell Death at Helmholtz Munich had been pioneering research in oxidative cell death for two and a half decades, making groundbreaking discoveries that have shaped our understanding of this unique form of cell death. Notably, their 2019 landmark discovery of the ferroptosis suppressor protein-1 (FSP1) as a second key ferroptosis suppressive system besides GPX4 was pivotal in driving major scientific advances and translational approaches in the field.
The FSP1 inhibitors tested in the studies by Palma et al. and Wu et al. were initially discovered in 2023 and now validated in close collaboration with Marcus Conrad and his team. His laboratory contributed both to the newly developed small-molecule inhibitors targeting FSP1 and to genetically engineered models used to validate their efficacy in vivo.
Original Publications
Palma et al., 2025: Lymph node environment drives FSP1 targetability in metastasizing melanoma. Nature. DOI: 10.1038/s41586-025-09709-1
Wu et al., 2025: Targeting FSP1 triggers ferroptosis in lung cancer. Nature. DOI: 10.1038/s41586-025-09710-8
