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NEDD9 confers ferroptosis resistance in liver cancer by inhibiting autophagy via the AKT‑mTOR signaling pathway
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DOI：10.1186/s13062-026-00927-9.png)
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Abstract
En 中文
Hepatocellular carcinoma (HCC), the most prevalent primary liver malignancy, is characterized by poor prognosis and limited therapeutic options. Ferroptosis, a recently identified form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a promising strategy for cancer therapy. Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) is a scaffold protein implicated in tumor progression; however, its role in the regulation of ferroptosis remains unclear. NEDD9 was overexpressed or knocked down in liver cancer cells using lentiviral vectors. RNA sequencing was performed to analyze transcriptomic changes. Cell viability and death were assessed using Cell Counting Kit-8 (CCK-8) and propidium iodide (PI) staining assays. C11-BODIPY 581/591, malondialdehyde (MDA), Western blot, dihydroethidium (DHE) and iron assays were used to detect lipid peroxidation, MDA content, protein expression, reactive oxygen species (ROS) and Fe²⁺ levels, respectively. Autophagy was modulated using Torin1 (activator) and chloroquine (inhibitor). For in vivo experiments, NEDD9‑knockdown Hepa1‑6 cells were subcutaneously injected into C57BL/6 mice to assess tumor growth and ferroptosis‑related sensitivity to sorafenib. RSL3- and sorafenib-induced ferroptosis in HCC cells was accompanied by a significant reduction in NEDD9 expression. NEDD9 overexpression upregulated glutathione peroxidase 4 (GPX4) and conferred resistance to ferroptosis, whereas NEDD9 knockdown decreased GPX4 expression, elevated ROS and MDA levels, and markedly sensitized cells to ferroptosis. Mechanistically, our findings support a model in which NEDD9-associated AKT-mTOR signaling contributes to ferroptosis resistance through the regulation of autophagy-related processes. More specifically, NEDD9 overexpression activated AKT-mTOR signaling and suppressed autophagy, thereby maintaining GPX4 abundance without altering intracellular Fe²⁺ levels, whereas autophagy activation attenuated NEDD9-mediated ferroptosis resistance. In contrast, NEDD9 knockdown attenuated AKT-mTOR signaling and was associated with lysosome-dependent GPX4 loss and intracellular Fe²⁺ accumulation. Pharmacological inhibition of autophagy reversed the ferroptosis-promoting effect caused by NEDD9 knockdown. In vivo, NEDD9 knockdown suppressed tumor growth and potentiated the antitumor efficacy of the ferroptosis‑inducing agent sorafenib. Ferroptosis in HCC cells was accompanied by decreased NEDD9 expression. NEDD9 overexpression markedly inhibited ferroptosis, whereas NEDD9 knockdown promoted it. These findings suggest that targeting NEDD9 may represent a potential strategy for enhancing the therapeutic response to ferroptosis-associated treatments in liver cancer.
Keywords:
Ferroptosis
NEDD9
AKT-mTOR
Autophagy
GPX4
Fe2+
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