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KRAS depletion suppresses ferroptosis and affects Hippo pathway in cataract
Hongda Jiang1, Yinggui Yu2, Yu Yan2
1Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China.
Abstract:
Cataract, a painless and progressive disorder is manifested as the opacification of the lens that represents the most significant cause of blindness worldwide. The objective of this study is to unveil the function of Kirsten rat sarcoma (KRAS) and potential action mechanisms against cataract. The ferroptosis-associated differentially expressed genes (DEGs) and pivot genes were extracted through the comprehensive bioinformatics methods. Erastin was applied for inducing ferroptosis in hydrogen peroxide (H2O2)-treated SRA01/04 cells, and validated by detecting content of intracellular iron, glutathione (GSH), malondialdehyde (MDA). Additionally, the effects of KRAS deficiency on ferroptosis were determined by functional assays. The proteins expression related to ferroptosis and Hippo pathway were determined by Western blotting. A total of 73 ferroptosis-related DEGs were discovered, and 6 critical core genes were confirmed upregulation in cataract cell model. The H2O2-treated SRA01/04 cells exhibited decrease of cell viability and proliferation, iron accumulation, MDA increase, GSH consumption, rise of COX2 and decline of GPX4, with further aggravated under erastin treatment, while the phenomena were improved by KRAS knockdown. Additionally, KRAS deficiency was involved in the Hippo signalling pathway activation. Downregulation of KRAS might restrain ferroptosis and affect Hippo pathway in cataract.
Insights
This study reveals Kirsten rat sarcoma (KRAS) plays a role in cataract development by influencing ferroptosis, a cell death process. Downregulating KRAS may offer a new therapeutic strategy for preventing vision loss from cataracts.
Area of Science:
- Ophthalmology
- Molecular Biology
- Biochemistry
Background:
- Cataract is a leading cause of global blindness, characterized by lens opacification.
- Understanding the molecular mechanisms underlying cataract formation is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the function of Kirsten rat sarcoma (KRAS) in cataract pathogenesis.
- To elucidate the potential mechanisms by which KRAS influences cataract development, particularly concerning ferroptosis.
Main Methods:
- Bioinformatic analysis to identify ferroptosis-associated differentially expressed genes (DEGs) and key genes in cataract.
- Induction of ferroptosis in SRA01/04 cells using hydrogen peroxide (H2O2) and erastin.
- Validation of ferroptosis by measuring intracellular iron, glutathione (GSH), and malondialdehyde (MDA) levels.
- Assessment of KRAS deficiency effects on ferroptosis and Hippo signaling pathway via functional assays and Western blotting.
Main Results:
- Identified 73 ferroptosis-related DEGs, with 6 core genes upregulated in a cataract cell model.
- H2O2-induced ferroptosis in SRA01/04 cells showed decreased viability, increased iron and MDA, decreased GSH, elevated COX2, and reduced GPX4.
- KRAS knockdown ameliorated these ferroptosis markers and was associated with Hippo signaling pathway activation.
Conclusions:
- KRAS plays a significant role in regulating ferroptosis in the context of cataract.
- Downregulation of KRAS may inhibit ferroptosis and modulate the Hippo signaling pathway, suggesting a potential therapeutic target for cataracts.
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