Open Access

ARTICLE

SLC16A1 Activates the STAT3/SLC7A11 Pathway to Mediate Ferroptosis Resistance and Tumor Progression in Head and Neck Squamous Cell Carcinoma

Chunhui Tian^1,2, Weipin Xie^1,2, Wen Li², Huaiyu Gu², Xuebao Liu², Busheng Tong^1,*, Yehai Liu^1,*, Huaiyuan Zong^3,*

1 Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
2 Department of Otorhinolaryngology Head and Neck Surgery, Suzhou Hospital Affiliated of Anhui Medical University, Suzhou, China
3 Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China

* Corresponding Authors: Busheng Tong. Email: ; Yehai Liu. Email: ; Huaiyuan Zong. Email:

(This article belongs to the Special Issue: Next-Generation Oncology: Unearthing and Validating Novel Therapeutic Targets)

Oncology Research 2026, 34(5), 34 https://doi.org/10.32604/or.2026.077171

Received 03 December 2025; Accepted 28 February 2026; Issue published 22 April 2026

Abstract

Background: In head and neck squamous cell carcinoma (HNSCC), solute carrier family 16 member 1 (SLC16A1) is associated with tumor advancement and reduced sensitivity to ferroptosis, yet the molecular basis of these effects remains unclear. This study seeks to uncover how SLC16A1 contributes to HNSCC tumorigenesis. Methods: To elucidate how SLC16A1 drives HNSCC progression via ferroptosis resistance, we performed RNA sequencing on SLC16A1-knockdown HNSCC cells and controls, followed by functional validation. We next systematically assessed the role of the candidate molecule solute carrier family 7 member 11 (SLC7A11) in HNSCC progression and resistance to ferroptosis using loss- and gain-of-function experiments in vitro and xenograft-based assays in vivo. Finally, we applied RNA interference and validated expression changes by quantitative real-time polymerase chain reaction and immunoblotting to map the signaling pathway by which SLC16A1 controls SLC7A11 expression. Results: Integrated RNA sequencing and functional assays identified SLC7A11 as a key downstream effector of SLC16A1. SLC7A11 mediates SLC16A1-driven tumor cell proliferation, ferroptosis resistance, and tumorigenesis. Mechanistically, SLC16A1 activates signal transducer and activator of transcription 3 (STAT3) to transcriptionally upregulate SLC7A11 expression. Conclusion: Our study defines a novel SLC16A1–STAT3–SLC7A11 signaling axis that promotes HNSCC progression by conferring robust resistance to ferroptosis. This axis may be leveraged as a therapeutic target to mitigate treatment resistance.

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Supplementary Material

Supplementary Material File

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