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NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer
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NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer
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Journal Article
NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer
2025
Overview
Cellular glutathione (GSH) in lung cancer cells represents the most abundant antioxidant. GSH production is regulated not only by upregulated cystine/glutamate exchanger (xCT) but also by the involvement of glutamate transporters, specifically excitatory amino acid transporter 3 (EAAT3). Our prior research established that the uptake of glutamate via EAAT3 plays a pivotal role in driving cystine uptake through xCT, contributing to GSH biosynthesis during lung tumorigenesis. Nevertheless, the underlying mechanism governing the upregulation of EAAT3 remains enigmatic. In this study, we conducted a comprehensive reanalysis of publicly available data and employed the Gprc5a
–/–
/SR-IκB mouse model alongside in vitro cell experiments to elucidate the correlations between NF-κB and EAAT3 in lung cancer. We observed that EAAT3 knockdown, similar to NF-κB inhibition, led to the accumulation of reactive oxygen species (ROS) and increased sensitivity to ferroptosis induction by RAS-selective lethal 3 (RSL3). Mechanistic insights were obtained through chromatin immunoprecipitation and luciferase reporter assays, revealing that NF-κB induces EAAT3 expression via two putative cis-elements within its promoter. Furthermore, our investigation unveiled the upregulation of EAAT3 in a subset of clinical non-small cell lung cancer (NSCLC) tissues, exhibiting a positive correlation with the P65 protein. In addition, the inflammatory factor of smoking was found to augment EAAT3 expression in both human and murine experimental models. These findings collectively emphasize the pivotal role of the NF-κB/EAAT3 axis in managing antioxidant stress and influencing lung cancer development. Moreover, this research offers insights into the potential for a combined ferroptosis therapy strategy in lung cancer treatment.
Highlights
NF-κB drives EAAT3 expression, key for GSH biosynthesis in lung cancer cells.
EAAT3 knockdown increases ROS and enhances sensitivity to ferroptosis in lung cancer.
EAAT3 upregulation in NSCLC tissues correlates with P65 protein levels.
Smoking-induced inflammation boosts EAAT3 expression in lung cancer models.
Potential for combined ferroptosis therapy targeting NF-κB/EAAT3 axis in lung cancer.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/105
/ 13/31
/ 13/51
/ 13/89
/ 14/35
/ 38/23
/ 42/109
/ 64/60
/ Animals
/ Biomedical and Life Sciences
/ Cancer
/ Excitatory Amino Acid Transporter 3 - genetics
/ Excitatory Amino Acid Transporter 3 - metabolism
/ Excitatory amino acid transporters
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Mice
/ Non-small cell lung carcinoma
/ Reactive Oxygen Species - metabolism
/ Smoking
