Open Access
ARTICLE
KNL1 Regulates Ferroptosis Resistance and Migration in Lung Adenocarcinoma Cells via AMPK-mTOR Signaling
Yiran Dong1, Jingyue Wang1, Jiayang Chen2, Liang Mo2, Yong You1,*
1 Research Laboratory of Translational Medicine, Hengyang Medical College, University of South China, Hengyang, China
2 Department of Thoracic Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
* Corresponding Author: Yong You. Email: 
(This article belongs to the Special Issue: Identification of potential targets and biomarkers for cancers and the exploration of novel molecular mechanisms of tumorigenesis and metastasis)
Oncology Research https://doi.org/10.32604/or.2026.075191
Received 27 October 2025; Accepted 16 January 2026; Published online 04 February 2026
Abstract
Background: Lung adenocarcinoma (LUAD), the most prevalent histological subtype of lung cancer, remains a leading cause of cancer-related mortality due to late diagnosis, metastasis, and therapy resistance. The aim of the study is to investigate the role of Kinetochore Scaffold 1 (KNL1) in promoting LUAD progression and its underlying molecular regulatory mechanisms. Methods: KNL1 mRNA expression levels across 33 cancer types were analyzed using bioinformatics analysis based on the TCGA database. Immunohistochemistry (IHC) was used to assess KNL1 expression in LUAD and normal tissues. Stable KNL1-knockdown and KNL1-overexpressing LUAD cell lines were established using lentiviral infection. Western blotting (WB) was used to measure epithelial-mesenchymal transition (EMT) markers and ferroptosis-related protein expression. Cell migration was evaluated via scratch wound healing assays. The thiobarbituric acid (TBA) method was employed for the detection of malondialdehyde. a fluorescent probe was utilized to determine ferrous ion content. WB determined the phosphorylation ratios of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) proteins. Results: 1. KNL1 was highly expressed in 31 cancer types, including LUAD. Kaplan-Meier curves showed significantly shorter median survival in patients with high KNL1 expression. IHC confirmed upregulated KNL1 expression in LUAD tissues. 2. KNL1 overexpression significantly promoted LUAD cell migration and increased mesenchymal marker expression, whereas KNL1 knockdown exerted opposite effects. 3. KNL1 overexpression significantly reduced MDA content and Fe2+ levels in RSL3-treated LUAD cells while increasing the expression of key ferroptosis defense proteins; conversely, it markedly increased the accumulation of MDA and Fe2+ and downregulated these proteins. KNL1 overexpression significantly increased phosphorylated AMPK (p-AMPK) expression but decreased phosphorylated mTOR (p-mTOR) expression in RSL3-treated LUAD cells; conversely, it inhibited p-AMPK expression and activated p-mTOR. Conclusion: KNL1 promotes lung adenocarcinoma progression by suppressing ferroptosis through regulation of the AMPK-mTOR signaling pathway.
Keywords
Kinetochore scaffold 1; ferroptosis; AMP-actived protein kinase-mammalian target of rapamycin signaling pathway; epithelial-mesenchymal transition; lung adenocarcinoma
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