Epigenetic Silencing of ZNF471 Contributes to Osimertinib Resistance in Lung Adenocarcinoma: β-Hydroxybutyrate Associates with ZNF471 Re-Expression and Reduced Resistance-Associated Phenotypes
4 affiliations
- 1Department of Pathology, Yueyang People’s Hospital of Hunan Normal University, Yueyang, China
- 2School of Basic Medical Sciences, Hunan Normal University Health Science Center, Hunan Normal University, Changsha, China
- 3Department of Orthopedics, Yueyang People’s Hospital of Hunan Normal University, Yueyang, China
- 4Department of Science and Education, Yueyang People’s Hospital of Hunan Normal University, Yueyang, China
Abstract
Background: Acquired resistance limits the benefit of osimertinib in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD), and epigenetic silencing may contribute to this process. This study aimed to determine whether promoter hypermethylation-associated silencing of zinc finger protein 471 (ZNF471) contributes to resistance and whether β-hydroxybutyrate (BHB) can restore ZNF471 expression. Methods: ZNF471 expression and promoter methylation were analyzed in public datasets, clinical samples, and osimertinib-sensitive and resistant cell lines. Functional assays and signaling analyses were performed in vitro, and BHB treatment and ZNF471 overexpression were evaluated in xenografts. Results: ZNF471 was downregulated and hypermethylated in LUAD, and low expression was associated with advanced stage and poor survival. ZNF471 restoration reduced the osimertinib half-maximal inhibitory concentration, inhibited migration, invasion, and tumorsphere formation, and was associated with suppression of PI3K/AKT/mTOR signaling, whereas ZNF471 knockdown had the opposite effect. BHB increased ZNF471 expression, reduced methylation-specific PCR signals, and synergized with osimertinib in resistant cells in vitro. In xenografts, BHB treatment and ZNF471 overexpression each inhibited tumor growth. Conclusions: ZNF471 is an epigenetically silenced modulator of osimertinib sensitivity in LUAD. BHB may enhance osimertinib response by reactivating ZNF471. ZNF471 is an epigenetically silenced modulator of osimertinib sensitivity in LUAD. BHB may enhance osimertinib response by reactivating ZNF471. Taken together, these findings suggest that BHB is associated with ZNF471 re-expression and reduced osimertinib resistance-associated phenotypes in LUAD cells, although whether ZNF471 is required for this effect remains to be determined.
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BibTeX
@article{feng2026epigenetic,
title = {{Epigenetic Silencing of ZNF471 Contributes to Osimertinib Resistance in Lung Adenocarcinoma: β-Hydroxybutyrate Associates with ZNF471 Re-Expression and Reduced Resistance-Associated Phenotypes}},
author = {Dade Feng and Huiting Yan and Qian Ni and Zirui Peng and Xiong Xu and Yanfang Liang and Chongmei Liu},
journal = {Oncology Research},
year = {2026},
month = oct,
doi = {10.32604/or.2026.087712},
url = {https://doi.org/10.32604/or.2026.087712},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epigenetic Silencing of ZNF471 Contributes to Osimertinib Resistance in Lung Adenocarcinoma: β-Hydroxybutyrate Associates with ZNF471 Re-Expression and Reduced Resistance-Associated Phenotypes
AU - Dade Feng
AU - Huiting Yan
AU - Qian Ni
AU - Zirui Peng
AU - Xiong Xu
AU - Yanfang Liang
AU - Chongmei Liu
PY - 2026
DA - 2026/10/28
JO - Oncology Research
DO - 10.32604/or.2026.087712
UR - https://doi.org/10.32604/or.2026.087712
AB - Background: Acquired resistance limits the benefit of osimertinib in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD), and epigenetic silencing may contribute to this process. This study aimed to determine whether promoter hypermethylation-associated silencing of zinc finger protein 471 (ZNF471) contributes to resistance and whether β-hydroxybutyrate (BHB) can restore ZNF471 expression. Methods: ZNF471 expression and promoter methylation were analyzed in public datasets, clinical samples, and osimertinib-sensitive and resistant cell lines. Functional assays and signaling analyses were performed in vitro, and BHB treatment and ZNF471 overexpression were evaluated in xenografts. Results: ZNF471 was downregulated and hypermethylated in LUAD, and low expression was associated with advanced stage and poor survival. ZNF471 restoration reduced the osimertinib half-maximal inhibitory concentration, inhibited migration, invasion, and tumorsphere formation, and was associated with suppression of PI3K/AKT/mTOR signaling, whereas ZNF471 knockdown had the opposite effect. BHB increased ZNF471 expression, reduced methylation-specific PCR signals, and synergized with osimertinib in resistant cells in vitro. In xenografts, BHB treatment and ZNF471 overexpression each inhibited tumor growth. Conclusions: ZNF471 is an epigenetically silenced modulator of osimertinib sensitivity in LUAD. BHB may enhance osimertinib response by reactivating ZNF471. ZNF471 is an epigenetically silenced modulator of osimertinib sensitivity in LUAD. BHB may enhance osimertinib response by reactivating ZNF471. Taken together, these findings suggest that BHB is associated with ZNF471 re-expression and reduced osimertinib resistance-associated phenotypes in LUAD cells, although whether ZNF471 is required for this effect remains to be determined.
SN - 0965-0407
SN - 1555-3906
ER -