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Updated: Jun 13, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation
Sophia M Lamperis1, Kaylin M McMahon1,2, Andrea E Calvert1,2
1Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611.
Abstract:
Ferroptosis is a cell death mechanism distinguished by its dependence on iron-mediated lipid oxidation. Cancer cells highly resistant to conventional therapies often demonstrate lipid metabolic and redox vulnerabilities that sensitize them to cell death by ferroptosis. These include a unique dependency on the lipid antioxidant selenoenzyme, glutathione peroxidase 4 (GPx4), that acts as a ferroptosis inhibitor. Synthetic high-density lipoprotein-like nanoparticle (HDL NP) targets the high-affinity HDL receptor scavenger receptor class B type 1 (SR-B1) and regulates cell and cell membrane lipid metabolism. Recently, we reported that targeting cancer cell SR-B1 with HDL NP depleted cell GPx4, which is accompanied by increased cell membrane lipid peroxidation and cancer cell death. These data suggest that HDL NP may induce ferroptosis. Thus, we conducted an unbiased CRISPR-based positive selection screen and target validation studies in ovarian clear cell carcinoma (OCCC) cell lines to ascertain the mechanism through which HDL NP regulates GPx4 and kills cancer cells. The screen revealed two genes, acyl-CoA synthetase long chain family member 4 (ACSL4) and thioredoxin reductase 1 (TXNRD1), whose loss conferred resistance to HDL NP. Validation of ACSL4 supports that HDL NP induces ferroptosis as the predominant mechanism of cell death, while validation of TXNRD1 revealed that HDL NP reduces cellular selenium and selenoprotein production, most notably, GPx4. Accordingly, we define cancer cell metabolic targets that can be simultaneously actuated by a multifunctional, synthetic HDL NP ligand of SR-B1 to kill cancer cells by ferroptosis.
Insights
Synthetic HDL nanoparticles induce ferroptosis, a cell death pathway, in ovarian cancer by targeting lipid metabolism and depleting glutathione peroxidase 4 (GPx4). This approach offers a novel strategy for cancer therapy.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Ferroptosis is an iron-dependent cell death mechanism crucial for targeting therapy-resistant cancers.
- Cancer cells exhibit lipid metabolic vulnerabilities exploitable for inducing ferroptosis.
- Glutathione peroxidase 4 (GPx4) is a key inhibitor of ferroptosis, essential for cancer cell survival.
Purpose of the Study:
- To elucidate the mechanism by which synthetic high-density lipoprotein-like nanoparticles (HDL NP) induce cancer cell death.
- To identify the specific metabolic targets of HDL NP in ovarian clear cell carcinoma (OCCC).
- To validate HDL NP's role in inducing ferroptosis.
Main Methods:
- Utilized CRISPR-based positive selection screens in OCCC cell lines.
- Performed target validation studies for identified genes.
- Investigated the impact of HDL NP on lipid metabolism, GPx4 levels, and cell death pathways.
Main Results:
- The screen identified acyl-CoA synthetase long chain family member 4 (ACSL4) and thioredoxin reductase 1 (TXNRD1) as critical for HDL NP sensitivity.
- Validation confirmed HDL NP induces ferroptosis, primarily mediated by ACSL4.
- HDL NP was shown to reduce cellular selenium and selenoprotein production, including GPx4, via TXNRD1.
Conclusions:
- HDL NP effectively targets SR-B1 to induce ferroptosis in cancer cells.
- HDL NP modulates cancer cell lipid metabolism and GPx4 levels, leading to cell death.
- This study defines metabolic targets for a multifunctional HDL NP to combat OCCC via ferroptosis.
