HIF-1α enhances ferroptosis resistance in anaplastic thyroid carcinoma by suppressing ACSL4-mediated lipid metabolic homeostasis.

Authors

Renjie Xie, Ruixue Geng, Yuchen Wang, Chenyue Zhan, Xinyue Deng, Yanting Duan, Juyong Liang, Jiafeng Wang, Ruimin Liang, Jingyan Ge, Minghua Ge, Xiaozheng Zhu

Published in

Cellular & molecular biology letters. Jun 27, 2026. Epub Jun 27, 2026.

Abstract

Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification of novel treatment strategies. The tumor hypoxic microenvironment serves as a key driver of ATC progression and drug resistance, in which the transcription factor hypoxia-inducible factor 1α (HIF-1α) orchestrates key processes in regulating tumor metabolism, immune evasion, and resistance to cell death. Ferroptosis is a novel iron-dependent form of programmed death, defined by excessive peroxidation of polyunsaturated fatty acid phospholipids (PUFA-PL) within cellular membranes.
In this study, cellular and xenograft models were employed to demonstrate that hypoxia confers ferroptosis resistance to ATC cells. Lipid metabolomics analysis revealed HIF-1α regulates lipid metabolism, and acyl-CoA synthase 4 (ACSL4) was identified as key lipid metabolism-related candidate. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to assess the binding of HIF-1α to the hypoxia-response element (HRE) within the ACSL4 promoter region. Flow cytometric analysis was performed to investigate how HIF-1α inhibition augments the antitumor immunogenicity of PD-1 blockade, as evidenced by enhanced intratumoral CD8⁺ T-cell infiltration and cytokine secretion.
This study identifies a key mechanism by which HIF-1α provides ferroptosis resistance in ATC under the intrinsically hypoxic tumor microenvironment. HIF-1α directly binds the HRE within the ACSL4 promoter, transcriptionally repressing ACSL4 and consequently curtailing PUFA-PL biosynthesis, thereby conferring ferroptosis resistance on ATC cells. In addition, combined treatment with HIF-1α inhibitor and PD-1 blockade effectively suppresses tumor progression and enhances intratumoral CD8⁺ T-cell infiltration.
This study elucidates the molecular mechanism by which HIF-1α mediates anti-ferroptosis in ATC through regulating lipid metabolism and proposes a promising therapeutic strategy in which HIF-1α inhibition acts synergistically with PD-1 blockade for the treatment of ATC.

PMID:
42365271
Bibliographic data and abstract were imported from PubMed on 28 Jun 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.