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Cancer BiologyNature
Peer-reviewed journal article

Targeting FSP1 triggers ferroptosis in lung cancer

Katherine WuiD, Alec J. VaughaniD, Jozef P. BossowskiiD, Yuan HaoiD, Aikaterini ZiogouiD, Seon Min KimiD, Tae Ha KimiD, Mari N. Nakamura, Ray PillaiiD, Mariana Camargo Silva ManciniiD, Sahith RajalingamiD, Mingqi HaniD, Toshitaka NakamuraiD, Lidong WangiD, Suckwoo Chung, Diane M. SimeoneiD, David B. ShackelfordiD, Yun Pyo KangiD, Marcus ConradiD, Thales Y. PapagiannakopoulosiD

Abstract

Pre-clinical and clinical studies have demonstrated how dietary antioxidants or mutations activating antioxidant metabolism promote cancer, highlighting a central role oxidative stress in tumorigenesis. However, it is unclear if oxidative stress ultimately increases to a point of cell death. Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death triggered by uncontrolled lipid peroxidation1-3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and if it can be leveraged therapeutically remains unknown4,5. Using genetically-engineered mouse models (GEMMs) of lung adenocarcinoma (LUAD), we performed tumor specific loss-of-function studies of the two key ferroptosis suppressors, glutathione peroxidase 4 (Gpx4)6,7 and ferroptosis suppressor protein 1 (Fsp1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumors 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 (Fsp1KO) tumors had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary, or pharmacological approaches effectively restored the growth of Fsp1KO tumors in vivo. Unlike GPX4, FSP1 expression was prognostic for disease progression and poorer survival in LUAD patients, 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 in lung cancer patients.

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Claude Opus 5.5 · xhigh effort · 5 Nov 2026 · from the full text of version 2 (23 Aug 2025) · CC BY-NC-ND 4.0

Genetic deletion or pharmacological inhibition of ferroptosis suppressor protein 1 (FSP1) induces lipid peroxidation and restricts lung adenocarcinoma growth in vivo, establishing FSP1 as a therapeutic vulnerability.

Although cancer cells are sensitive to ferroptosis in vitro, GPX4 inhibitors suffer from systemic toxicity and poor bioavailability, while FSP1 was previously considered redundant when GPX4 is intact. Demonstrating that lung tumors uniquely require FSP1 in vivo and respond to icFSP1 monotherapy establishes a less toxic, actionable therapeutic target for lung adenocarcinoma.

Key results

  1. ShownGenetic deletion of either Gpx4 or Fsp1 in autochthonous Kras/Tp53-mutant lung tumors markedly reduces tumor burden and malignant progression from adenoma to adenocarcinoma by triggering lipid peroxidation and ferroptosis.

    In KP GEMMs, sgGpx4 (n=7) and sgFsp1 (n=6) significantly reduced lung tumor burden and increased adenoma-to-adenocarcinoma ratios vs sgNeo controls (n=4-6), with <15% Gpx4+ and <5% Fsp1+ residual staining, elevated 4-HNE and TUNEL staining, and rescue by 10 mg/kg liproxstatin-1 (LIP1). · GPX4 prevents ferroptosis in lung tumors; Fsp1 is required for lung tumorigenesis; Figure legends

  2. ShownUnlike GPX4, FSP1 expression increases during lung adenocarcinoma progression and correlates with worse overall survival in patients with KRAS-mutant tumors.

    In TCGA KRAS-mutant LUAD patients (n=280), high FSP1 (AIFM2) expression was associated with shorter median survival of 1215 days vs 1498 days for low FSP1 (hazard ratio 1.51 [1.01-2.25]), whereas GPX4 expression showed no survival correlation (n=464); Fsp1 protein also rose from 10 to 14 weeks in KP GEMM tumors. · Unlike GPX4, FSP1 is upregulated in LUAD; TCGA analyses; Figure legends

  3. ShownCancer cells require FSP1 to suppress ferroptosis specifically in vivo across diverse oncogenic drivers, co-mutations, and tissue lineages, whereas FSP1 is dispensable in vitro when GPX4 is intact.

    CRISPR/Cas9 FSP1 knockout did not impair baseline in vitro viability without RSL3, but significantly suppressed subcutaneous or orthotopic tumor growth in vivo in murine KP (n=8 vs n=7 WT), 16645 (n=7 vs 9), and KPC7 PDAC (n=9 vs 10) models and human H2009, H1299, PC9, H1975, and A549 xenografts (n=8-10 per group). · Fsp1 is required uniquely in vivo; FSP1 dependency is not mutation-specific; Figure legends

  4. ShownFsp1-knockout tumors accumulate oxidized phospholipids and show depleted reduced CoQ9H2, and their in vivo growth is restored by Gpx4 overexpression, Acsl4 deletion, dietary vitamin E, or liproxstatin-1.

    Orthotopic Fsp1^KO tumors had elevated oxidized PC/PE species and lower CoQ9H2/CoQ9 ratios by LC-MS; tumor burden and growth were significantly rescued by Gpx4^OE (n=8), sgAcsl4 co-deletion (n=7), high vitamin E diet (n=6-8), or daily LIP1 treatment (n=6-7). · Ferroptosis inhibition rescues Fsp1 loss; Figure legends

  5. ShownPharmacological inhibition of human FSP1 with icFSP1 suppresses tumor growth and extends survival in vivo via on-target ferroptosis induction.

    Twice-daily 50 mg/kg icFSP1 monotherapy significantly extended survival and reduced tumor growth in mice bearing hFSP1^WT-expressing KP lung tumors (n=5-8; abrogated by LIP1 co-treatment or drug-resistant hFSP1^Q319K mutation, n=7) and suppressed KRAS^G12D/TP53-mutant LX465 patient-derived xenograft growth (n=10 vs 10 vehicle). · FSP1 inhibition extends overall survival; Antioxidant/drug treatments; Figure legends

Methods, data and reproducibility

Performed CRISPR/Cas9 loss- and gain-of-function studies of Gpx4, Fsp1, and Acsl4 in autochthonous Kras^(LSL-G12D/+); Tp53^(fl/fl); Rosa26^(LSL-Cas9/LSL-Cas9) (KP) mouse lung adenocarcinoma models, syngeneic grafts, human LUAD/PDAC xenografts, and a PDX. Combined LC-MS/MS oxidized phospholipidomics and CoQ9H2/CoQ9 profiling, TCGA survival analyses, vitamin E or liproxstatin-1 rescue, and in vivo icFSP1 treatment.

  • Primary lung adenocarcinoma (LUAD) tumor gene expression, mutation, and clinical survival profiles from The Cancer Genome Atlas (TCGA) · human · n = 515 LUAD patients (n=464 for overall survival; n=280 KRAS-mutant survival) · https://TCGute.org
  • Autochthonous Kras^(LSL-G12D/+); Tp53^(fl/fl); Rosa26^(LSL-Cas9/LSL-Cas9) (KP) lung adenocarcinoma genetically engineered mouse models and syngeneic/xenograft transplants · mouse · n = >= 4 mice per experimental condition · JAX strain #000664
  • Human and murine LUAD and PDAC cell lines (KP, H2009, H1299, PC9, H1975, A549, 16645, KPC7) and LUAD patient-derived xenograft LX465 · human and mouse · n = 7 cell lines in xenograft panel plus KP and PDX LX465
  • LC-MS oxidized phospholipidomics and CoQ9/CoQ9H2 profiles of KP orthotopic lung tumors and cultured cells · mouse · MSV000098883
Methods & tools
CRISPick, QuPath, Living Image, Lipostar2, LPPtiger2, Skyline, EL-MAVEN, PhenoImagerHT 2.0, Phenochart 2.0, InForm 3.0, FlowJo, GraphPad Prism
Data & accessions
https://massive.ucsd.edu/https://tcgute.org/https://gdc.cancer.gov/about-data/publications/pancanatlas
Reagents & environment
Skyline (v24.1), EL-MAVEN (v0.12.0), PhenoImagerHT 2.0, Phenochart 2.0, InForm 3.0, FlowJo version 10, GraphPad Prism v9
Reproducibility gaps
Other materials are available upon request from the corresponding author; no analysis code repository is reported.
Limitations (3)
  • Because icFSP1 selectively inhibits human FSP1 rather than murine Fsp1, in vivo monotherapy efficacy in immunocompetent mice required a hybrid KP tumor model ectopically expressing human FSP1 in Fsp1-knockout cells. · stated by the authors
  • Although flow cytometry showed no major shifts in broad immune populations upon icFSP1 treatment, more granular immune profiling is required to evaluate potential effects and side effects of FSP1 inhibition on the tumor microenvironment. · stated by the authors
  • Sample sizes for animal experiments were chosen based on prior experience rather than formal statistical power calculations, and investigators were not blinded during most data collection and analysis outside of histology and lipidomics. · stated by the authors

Who should read:Read this if you study ferroptosis regulation, lipid peroxidation metabolism, or preclinical therapeutic targets in genetically engineered and xenograft models of lung adenocarcinoma.

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