ACSL4 upregulates IFI44 and IFI44L expression - promotes the proliferation and invasiveness of head and neck squamous cell carcinoma cells

Sep 21, 2026

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Reprogramming cellular energy metabolism, including deregulated lipid metabolism, is a hallmark of head and neck squamous cell carcinoma (HNSCC), yet the mechanisms remain unclear. Long-chain acyl-CoA synthetase 4 (ACSL4) forms fatty acyl-CoAs for phospholipids or triglycerides. ACSL4 is highly expressed in HNSCC, correlating with poor patient survival, and its knockdown reduces proliferation and invasiveness. RNA sequencing highlights interferon-induced protein 44 (IFI44) and IFI44L as ACSL4 effectors via IFN signaling through JAK1/TYK2/STAT1 and IRF1.

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Abstract

Introduction

Background and Rationale

DOI: 10. 1111/cas.16236 OR I G I NAL ART I C L E ACSL4 upregulates IFI44 and IFI44L expression and promotes the proliferation and invasiveness of head and neck squamous cell carcinoma cells Darius Rupa1 | Hao-Wen Chuang2 | Chung-En Hu1 | Wen-Min Su1 | Shiou-Rong Wu2 | Herng-Sheng Lee2 | Ta-Chun Yuan1 1Department of Life Science, National Dong Hwa University, Hualien, Taiwan, ROC 2Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC Correspondence Ta-Chun Yuan, Department of Life Science, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Road, Shoufeng, Hualien 974301, Taiwan, ROC. [Email:](Email: yuan415@gms. ndhu.edu.tw)[ yuan415@gms. ndhu.edu.tw](Email: yuan415@gms. ndhu.edu.tw) Present address Darius Rupa, Department of Biology Education, Borneo Tarakan University, Indonesia Funding information Hsinchu Science Park Bureau, Ministry of Science and Technology, Taiwan, Grant/Award Number: NSC-111-2314-B- 259-001 and NSC-112-2314-B-259-001 Abstract Reprogramming of cellular energy metabolism, including deregulated lipid metabolism, is a hallmark of head and neck squamous cell carcinoma (HNSCC) . However, the underlying molecular mechanisms remain unclear. Long-chain acyl-CoA synthetase 4 (ACSL4), which catalyzes fatty acids to form fatty acyl-CoAs, is critical for synthesizing phospholipids or triglycerides. Despite the differing roles of ACSL4 in cancers, our data showed that ACSL4 was highly expressed in HNSCC tissues, positively correlating with poor survival rates in patients. Knockdown of ACSL4 in HNSCC cells led to reduced cell proliferation and invasiveness. RNA sequencing analyses identified interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), encoded by two interferon-stimulated genes, as potential effectors of ACSL4 . Silencing IFI44 or IFI44L expression in HNSCC cells decreased cell proliferation and invasiveness. Manipulating ACSL4 expression or activity modulated the expression levels of JAK1, tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 1 (STAT1), interferon α (IFNα), IFNβ, and interferon regulatory factor 1 (IRF1), which regulate IFI44 and IFI44L expression. Knockdown of IRF1 reduced the expression of JAK1, TYK2, IFNα , IFNβ, IFI44, or IFI44L and diminished cell proliferation and invasiveness. Our results suggest that ACSL4 upregulates interferon signaling, enhancing IFI44 and IFI44L expression and promoting HNSCC cell proliferation and invasiveness. Thus, ACSL4 could serve as a novel therapeutic target for HNSCC. K E Y WO R D S ACSL4, HNSCC, IFI44, IFI44L, IFNα/β, IRF1 Darius Rupa and Hao-Wen Chuang contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2024 The Author(s) . Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 1 | INTRODUCTION Lipids, composed of fatty acids (FAs), play essential roles in biomembrane formation, energy metabolism, and cellular signaling. Deregulated FA metabolism caused by aberrant expression or activation of metabolic enzymes drives FA overproduction, leading to metabolic disorders and cancer development. Long-chain acylCoA synthetases (ACSLs), including ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6, are essential for generating 12–20 carbon-contained long-chain fatty acyl-CoAs. Among them, ACSL4 is a unique ACSL that catalyzes the incorporation of polyunsaturated FAs into phospholipids. Furthermore, ACSL4 functions as a key modulator offerroptosis, a cell death process caused by the iron-dependent peroxidation of lipids. Accumulating evidence indicates that ACSL4 is highly expressed in multiple cancer types, includ

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Why might ACSL4 be considered a therapeutic target for HNSCC?

Because ACSL4 upregulates interferon signaling to increase IFI44 and IFI44L, driving HNSCC cell proliferation and invasiveness, it offers a mechanistic target for intervention.

Sep 21, 2026

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