ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling

Tang, Zhihua; Shi, Yueli; Jiang, Xinyuan; Jiang, Sujing; Maihemuti, Nueraili; Zhang, Jie; Tang, Bufu; Xu, Zhiyong

doi:10.3390/biomedicines14061262

Open AccessArticle

ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling

by

Zhihua Tang

^1,2,†,

Yueli Shi

^3,†,

Xinyuan Jiang

⁴,

Sujing Jiang

⁴,

Nueraili Maihemuti

⁴,

Jie Zhang

^5,*

,

Bufu Tang

^6,* and

Zhiyong Xu

^1,3,*

¹

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

²

Department of Pharmacy, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing 312000, China

³

Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China

⁴

The Fourth Affiliated Hospital of School of Medicine, International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China

⁵

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China

⁶

Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this study.

Biomedicines 2026, 14(6), 1262; https://doi.org/10.3390/biomedicines14061262

Submission received: 30 March 2026 / Revised: 25 May 2026 / Accepted: 25 May 2026 / Published: 1 June 2026

(This article belongs to the Special Issue Advances in Lung Cancer: From Bench to Bedside (2nd Edition))

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Abstract

Background: Zinc homeostasis regulated by ZIP transporters is critical for tumor glycolytic reprogramming and progression, yet the role of specific ZIP family members in lung adenocarcinoma (LUAD) remains unclear. This study aimed to identify the key ZIP transporter in LUAD and elucidate its molecular mechanisms and therapeutic value. Methods: siRNA-based functional screening of the ZIP family was performed in A549 and PC9 cells. A combination of in vitro cellular assays, in vivo animal models, clinical sample analysis and bioinformatics was used to validate the function of ZIP7 and explore its regulatory mechanisms. Results: ZIP7 (SLC39A7) was identified as a critical driver of glycolysis and proliferation in LUAD. It was significantly upregulated in LUAD tissues and cell lines. Mechanistically, ZIP7 increased inhibitory phosphorylation of GSK3β at Ser9 to stabilize NRF2, maintained low intracellular ROS levels, and sustained mTOR signaling to promote glycolytic flux. ZIP7-induced lactate secretion also drove M2-like macrophage polarization and PD-L1 upregulation to establish an immunosuppressive microenvironment. Notably, genetic or pharmacological inhibition of ZIP7 markedly enhanced the antitumor efficacy of anti-PD-1 therapy in vivo. Conclusions: ZIP7 is a pivotal oncogenic zinc transporter in LUAD that drives tumor progression via metabolic reprogramming and immune remodeling. Targeting ZIP7 represents a promising strategy to improve the efficacy of anti-PD-1 immunotherapy for LUAD.

Keywords: lung adenocarcinoma; ZIP7; glycolysis; NRF2; tumor-associated macrophages; anti-PD-1 therapy

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MDPI and ACS Style

Tang, Z.; Shi, Y.; Jiang, X.; Jiang, S.; Maihemuti, N.; Zhang, J.; Tang, B.; Xu, Z. ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling. Biomedicines 2026, 14, 1262. https://doi.org/10.3390/biomedicines14061262

AMA Style

Tang Z, Shi Y, Jiang X, Jiang S, Maihemuti N, Zhang J, Tang B, Xu Z. ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling. Biomedicines. 2026; 14(6):1262. https://doi.org/10.3390/biomedicines14061262

Chicago/Turabian Style

Tang, Zhihua, Yueli Shi, Xinyuan Jiang, Sujing Jiang, Nueraili Maihemuti, Jie Zhang, Bufu Tang, and Zhiyong Xu. 2026. "ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling" Biomedicines 14, no. 6: 1262. https://doi.org/10.3390/biomedicines14061262

APA Style

Tang, Z., Shi, Y., Jiang, X., Jiang, S., Maihemuti, N., Zhang, J., Tang, B., & Xu, Z. (2026). ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling. Biomedicines, 14(6), 1262. https://doi.org/10.3390/biomedicines14061262

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ZIP7 Drives Glycolytic Reprogramming and Lactate-Mediated Immune Remodeling in Lung Adenocarcinoma Through GSK3β-NRF2 Signaling

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