---
title: "SIRT6 modulation of Nrf2 enhances cisplatin response in lung cancer models"
id: "pubmed-42727479"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42727479"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42727479/"
doi: "10.1016/j.bbrc.2026.154563"
published_at: "2026-10-22T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# SIRT6 modulation of Nrf2 enhances cisplatin response in lung cancer models
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42727479
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42727479/)
- **DOI:** [10.1016/j.bbrc.2026.154563](https://doi.org/10.1016%2Fj.bbrc.2026.154563)
- **Published At:** 2026-10-22T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study investigated whether **SIRT6** regulates **Nrf2** in a state-dependent manner and whether that regulation affects response to **cisplatin** in lung cancer models. - Investigators used clinical database analyses, genetic and pharmacologic interventions, two lung cancer cell lines (A549, HCC827), and an A549 xenograft model to probe the relationship. - High **NFE2L2** expression and a low-SIRT6/high-**NFE2L2** pattern correlated with worse clinical outcomes, the authors reported. - Experimental activation of **Nrf2** (overexpression or tBHQ) reduced cisplatin sensitivity in cell models, according to the data. - Enhancing **SIRT6** activity (overexpression or MDL-800 treatment) or inhibiting **Nrf2** improved cisplatin response in vitro; MDL-800 potentiated cisplatin tumor suppression in xenografts. - Biochemical assays indicated **SIRT6** modestly raised basal ARE activity but suppressed ARE transcription driven by **Nrf2** overexpression, tBHQ, or CBP; this suppression occurred despite proteasome or ubiquitination-pathway blockade. - Suppression associated with decreased Nrf2 acetyl-lysine signal and reduced nuclear accumulation of **Nrf2**, the authors observed. - Mutational analysis implicated a K599/K603/K604 cluster in **Nrf2** as functionally relevant to SIRT6 sensitivity; SIRT6 point mutants G60A and R65A showed differential inhibitory activity, but catalytic context complexity prevented assigning a specific enzymatic mechanism. - The source did not report detailed dosing regimens, treatment durations, or quantitative effect sizes in the abstract, and it did not establish direct deacetylation of Nrf2 by SIRT6.
## Clinical Analysis & Structured Key Points
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Epub 2026 Sep 9. # SIRT6 restrains hyperactivated Nrf2 to enhance cisplatin response in lung cancer models [Zhengpan Xiao](https://pubmed.ncbi.nlm.nih.gov/?term=Xiao+Z&cauthor_id=42727479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#full-view-affiliation-1 "Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Pathology, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China."), [Wanmeng Fu](https://pubmed.ncbi.nlm.nih.gov/?term=Fu+W&cauthor_id=42727479)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#full-view-affiliation-2 "Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, 570311, China."), [Shuangshuang Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+S&cauthor_id=42727479)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#full-view-affiliation-3 "Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China."), [Yechun Pei](https://pubmed.ncbi.nlm.nih.gov/?term=Pei+Y&cauthor_id=42727479)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#full-view-affiliation-3 "Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China."), [Yi Min](https://pubmed.ncbi.nlm.nih.gov/?term=Min+Y&cauthor_id=42727479)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#full-view-affiliation-4 "Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China. Electronic address: 992601@hainanu.edu.cn."), [Dayong Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+D&cauthor_id=42727479)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#full-view-affiliation-5 "Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China. Electronic address: wandy@hainanu.edu.cn.") Affiliations Expand ### Affiliations * 1 Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Pathology, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China. * 2 Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, 570311, China. * 3 Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China. * 4 Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China. Electronic address: 992601@hainanu.edu.cn. * 5 Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China. Electronic address: wandy@hainanu.edu.cn. * PMID: **42727479** * DOI: [ 10.1016/j.bbrc.2026.154563 ](https://doi.org/10.1016/j.bbrc.2026.154563) Item in Clipboard # SIRT6 restrains hyperactivated Nrf2 to enhance cisplatin response in lung cancer models Zhengpan Xiao et al. Biochem Biophys Res Commun. 2026. Show details Display options Display options Format Abstract PubMed PMID Biochem Biophys Res Commun Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Biochem+Biophys+Res+Commun%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Biochem+Biophys+Res+Commun%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42727479/) . 2026 Oct 22:836:154563. doi: 10.1016/j.bbrc.2026.154563. Epub 2026 Sep 9. ### Authors [Zhengpan Xiao](https://pubmed.ncbi.nlm.nih.gov/?term=Xiao+Z&cauthor_id=42727479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#short-view-affiliation-1 "Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Pathology, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China."), [Wanmeng Fu](https://pubmed.ncbi.nlm.nih.gov/?term=Fu+W&cauthor_id=42727479)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#short-view-affiliation-2 "Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, 570311, China."), [Shuangshuang Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+S&cauthor_id=42727479)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#short-view-affiliation-3 "Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China."), [Yechun Pei](https://pubmed.ncbi.nlm.nih.gov/?term=Pei+Y&cauthor_id=42727479)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#short-view-affiliation-3 "Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China."), [Yi Min](https://pubmed.ncbi.nlm.nih.gov/?term=Min+Y&cauthor_id=42727479)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#short-view-affiliation-4 "Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China. Electronic address: 992601@hainanu.edu.cn."), [Dayong Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+D&cauthor_id=42727479)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42727479/#short-view-affiliation-5 "Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China. Electronic address: wandy@hainanu.edu.cn.") ### Affiliations * 1 Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Pathology, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China. * 2 Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Central Laboratory, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, 570311, China. * 3 Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China. * 4 Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China; Department of Biotechnology, School of Life and Health, Hainan University, Haikou, 570228, China. Electronic address: 992601@hainanu.edu.cn. * 5 Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Laboratory of Biopharmaceuticals and Molecular Pharmacology, One Health Cooperative Innovation Center, Hainan University, Haikou, 570228, China. Electronic address: wandy@hainanu.edu.cn. * PMID: **42727479** * DOI: [ 10.1016/j.bbrc.2026.154563 ](https://doi.org/10.1016/j.bbrc.2026.154563) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Persistent Nrf2 activation promotes tumor adaptation and chemoresistance, but mechanisms that restrain excessive Nrf2 signaling remain unclear. We investigated whether SIRT6 regulates Nrf2 in a state-dependent manner and influences cisplatin response using clinical database analyses, genetic and pharmacological interventions, A549 and HCC827 cells, and an A549 xenograft model. High NFE2L2 expression and a low-SIRT6/high-NFE2L2 pattern were associated with unfavorable outcomes. Nrf2 overexpression or tBHQ activation reduced cisplatin sensitivity, whereas SIRT6 overexpression, MDL-800 treatment, or Nrf2 inhibition enhanced cisplatin response. In xenografts, MDL-800 enhanced cisplatin-induced tumor suppression and partially reversed the protective effect of tBHQ. SIRT6 modestly increased basal ARE activity but suppressed transcription activated by Nrf2 overexpression, tBHQ, or CBP. This suppression persisted after proteasome or ubiquitination-pathway inhibition and was accompanied by reduced Nrf2 acetyl-lysine signal and nuclear accumulation. G60A retained inhibitory activity, whereas R65A showed markedly reduced inhibition; however, their context-dependent catalytic properties preclude assignment of a specific enzymatic mechanism and do not establish direct Nrf2 deacetylation. Mutational analysis functionally implicated the K599/K603/K604 cluster in SIRT6-sensitive regulation. Together, these findings identify a state-dependent SIRT6-Nrf2 relationship and suggest that SIRT6 restrains excessive Nrf2 activity through an acetylation-linked mechanism, thereby enhancing cisplatin response in lung cancer models. **Keywords:** Chemoresistance; Deacetylation; Lung cancer; Neh3 domain; Nrf2; SIRT6. Copyright © 2026 Elsevier Inc. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## MeSH terms * A549 Cells Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22A549+Cells%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=A549+Cells) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42727479/) * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42727
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