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Loss of ACSL1 fuels ferroptosis resistance in clear cell renal carcinoma
Shangguo Wang1, Yuxiong Wang1, Bin Liu1
1Department of Urology II, The First Hospital of Jilin University, Changchun, Jilin, China.
Background:
Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cell death-has gained attention as a therapeutic strategy. This study investigates the role of ACSL1, a key lipid metabolism enzyme, in ccRCC.
Methods:
Using TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence, ACSL1 expression and clinical significance were analyzed. Functional assays with ACSL1-overexpressing ccRCC cells and a xenograft mouse model evaluated its impact on tumor behavior. Transcriptomics and lipidomics, alongside ROS, ferroptosis, and p53 inhibitors, were applied to uncover mechanisms.
Results:
ACSL1 is markedly downregulated in ccRCC and predicts poor prognosis. Overexpression suppressed proliferation and migration, induced cell death, and slowed tumor growth. Mechanistically, ACSL1 elevated ROS, activated p53, downregulated SLC7A11/GPX4, and triggered ferroptosis. Blocking ROS or p53 reversed these effects, confirming a ROS-p53-SLC7A11/GPX4 feedback loop.
Conclusion:
ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis via the ROS-p53-SLC7A11/GPX4 axis. It holds promise as a prognostic biomarker and therapeutic target in ccRCC.
Insights
Acyl-CoA synthetase long-chain family member 1 (ACSL1) acts as a tumor suppressor in clear cell renal cell carcinoma (ccRCC). Its downregulation promotes ccRCC progression, while restoration induces ferroptosis, offering a potential therapeutic strategy for kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Clear cell renal cell carcinoma (ccRCC) is the predominant kidney cancer subtype, characterized by altered lipid metabolism and resistance to therapies.
- Ferroptosis, a form of cell death driven by lipid peroxidation, is an emerging therapeutic avenue for cancer treatment.
- Acyl-CoA synthetase long-chain family member 1 (ACSL1), a crucial enzyme in lipid metabolism, is investigated for its role in ccRCC.
Purpose of the Study:
- To investigate the expression and function of ACSL1 in ccRCC.
- To elucidate the underlying mechanisms by which ACSL1 influences ccRCC progression and cell death.
- To evaluate ACSL1 as a potential prognostic biomarker and therapeutic target for ccRCC.
Main Methods:
- Analysis of ACSL1 expression in TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence.
- Functional assays involving ACSL1-overexpressing ccRCC cells and a xenograft mouse model.
- Transcriptomic and lipidomic analyses, alongside experiments using reactive oxygen species (ROS), ferroptosis, and p53 inhibitors.
Main Results:
- ACSL1 expression is significantly downregulated in ccRCC, correlating with a poor prognosis.
- ACSL1 overexpression inhibited ccRCC cell proliferation and migration, reduced tumor growth, and induced cell death.
- ACSL1 promotes ferroptosis by elevating ROS, activating p53, and downregulating SLC7A11/GPX4, establishing a ROS-p53-SLC7A11/GPX4 feedback loop.
Conclusions:
- ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis through the ROS-p53-SLC7A11/GPX4 pathway.
- ACSL1 demonstrates potential as a prognostic biomarker and a therapeutic target for ccRCC treatment.
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