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

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.