Turning off FSP1 forces lung cancer cells to collapse under their own stress, sharply reducing tumor growth.
Researchers at NYU Langone Health have discovered that a specific form of cell death triggered by the buildup of highly reactive molecules can help slow the growth of lung tumors.
This form of cell death, called ferroptosis, originally developed as a natural way for the body to remove cells experiencing extreme stress. Cancer cells also undergo this stress, yet they have adapted over time by developing defenses that prevent ferroptosis, allowing them to continue multiplying even when they are damaged.
Blocking FSP1 Greatly Reduces Lung Tumor Growth
A study published online November 5 in Nature reported that an experimental approach capable of blocking a protein known as ferroptosis suppressor protein 1 (FSP1) significantly reduced tumor growth in mice with lung adenocarcinoma (LUAD). Preventing FSP1 from functioning in cancer cells reduced tumor size by up to 80%. Lung cancer remains the leading cause of cancer-related deaths worldwide, and LUAD is the most common type among nonsmokers, accounting for about 40% of all cases.
“This first test of a drug that blocks ferroptosis suppression highlights the importance of the process to cancer cell survival and paves the way for a new treatment strategy,” said senior study author Thales Papagiannakopoulos, PhD, an associate professor in the Department of Pathology at the NYU Grossman School of Medicine.
How Reactive Molecules Drive Ferroptosis
Ferroptosis occurs when iron builds up inside cells and fuels the creation of highly reactive molecules made from oxygen, water, and hydrogen peroxide known as reactive oxygen species (ROS). These molecules are important for basic cell communication, but in excess they contribute to oxidative stress, a harmful process in which ROS oxidize (add oxygen molecules to) delicate proteins and DNA, damaging or breaking them apart. ROS also harm the fats that form cell membranes, leading to cell death and tissue injury.
Genetic and Drug-Based Approaches Strengthen Ferroptosis
In the new study, researchers engineered mice so their lung cancer cells lacked the FSP1 gene. Without this gene, tumors became smaller and cancer cell death increased. The team also tested a newer type of drug known as an FSP1 inhibitor, called icFSP1. Mice treated with icFSP1 lived longer and experienced tumor reductions similar to those observed in mice whose tumors had been genetically altered to remove FSP1.
Why FSP1 May Be a Better Therapeutic Target Than GPX4
The findings also indicate that FSP1 could be a more promising target for future cancer therapies than glutathione peroxidase 4 (GPX4), another protein known to prevent ferroptosis. FSP1 played a larger role in blocking ferroptosis in lung cancer cells specifically, while GPX4 appeared more essential in normal cell activity (which may reduce the risk of side effects). The study also found that elevated levels of FSP1 were linked to lower survival rates in human patients with LUAD, a pattern not seen with GPX4.
“Our future research will focus on optimizing FSP1 inhibitors and investigating the potential of harnessing ferroptosis as a treatment strategy for other solid tumors, such as pancreatic cancer,” said lead study author Katherine Wu, an MD/PhD student working in the Papagiannakopoulos lab. “We aim to translate these findings from the lab into novel clinical therapies for cancer patients.”
Reference: “Targeting FSP1 triggers ferroptosis in lung cancer” by Katherine Wu, Alec J. Vaughan, Jozef P. Bossowski, Yuan Hao, Aikaterini Ziogou, Seon Min Kim, Tae Ha Kim, Mari N. Nakamura, Ray Pillai, Mariana Mancini, Sahith Rajalingam, Mingqi Han, Toshitaka Nakamura, Lidong Wang, Suckwoo Chung, Diane Simeone, David Shackelford, Yun Pyo Kang, Marcus Conrad and Thales Papagiannakopoulos, 5 November 2025, Nature.
DOI: 10.1038/s41586-025-09710-8
Along with Wu and Pagagiannakopoulos, study authors from the Department of Pathology at NYU Langone are co-first author Alec Vaughan, Jozef Bossowski, Yuan Hao, Aikaterini Ziogou, Mari Nakamura, Ray Pillai, Mariana Mancini, Sahith Rajalingam, and Suckwoo Chung. Also study authors are Seon Min Kim, Tae Ha Kim, and Yun Pyo Kang of the College of Pharmacy and Research Institute of Pharmaceutical Sciences at Seoul National University; Mingqi Han and David Shackelford in the Department of Pulmonary and Critical Care Medicine at the David Geffen School of Medicine, University of California Los Angeles; Toshitaka Nakamura and Marcus Conrad from the Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, at Helmholtz Munich in Germany, and Lidong Wang and Diane Simeone from the Moores Cancer Center, University of California, San Diego, La Jolla.
The study was funded by National Institutes of Health grants S10RR027926, S10OD032292, R37CA222504, R01CA227649, R01CA283049, R01CA262562, T32GM136542, T32GM136573, and T32GM136542. Also providing support for the work were American Cancer Society Research Scholar Grant (RSG-17-20001–TBE), Ruth L. Kirschstein Individual Predoctoral National Research Service Award fellowship (F30CA275258), Deutsche Forschungsgemeinschaft (DFG) (CO 291/7-1 Priority Program SPP 2306 [CO 291/9-1, #461385412; CO 291/10-1, #461507177], the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant GA 884754), and Perlmutter Cancer Center Support Grant P30CA016087.
Papagiannakopoulos received funding from the Pfizer Medical Education Group, Dracen Pharmaceuticals, Kymera Therapeutics, Bristol Myers Squibb, and Agios, available under a CC-BY-NC-ND 4.0 international license. The relationships are being managed in accordance with NYU Langone Health policies.
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