PLOD1 Drives Head and Neck Squamous Cell Carcinoma Progression Through P4HA2-Mediated Activation of the...

Some subtypes of head and neck squamous cell carcinoma (HNSCC) exhibit aggressive progression and poor prognosis, underscoring the need for novel therapeutic targets. While procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is implicated in tumour collagen remodelling, its functional role and regulatory mechanisms in HNSCC remain elusive. PLOD1 expression and clinical relevance were analysed using TCGA-HNSC data, patient tissues and cell lines. Functional impacts were assessed via in vitro assays (CCK-8, flow cytometry, Transwell) and in vivo xenograft models. Mechanistic insights were explored through co-immunoprecipitation, Western blotting, bioinformatics and pharmacological inhibition. PLOD1 was significantly upregulated in HNSCC tissues and correlated with adverse clinical outcomes. In vitro, PLOD1 overexpression potentiated proliferation, invasion and cell cycle progression while suppressing apoptosis; PLOD1 knockdown elicited opposing effects. PLOD1 activated the FAK/PI3K/AKT/mTOR pathway and directly interacted with prolyl 4-hydroxylase subunit alpha 2 (P4HA2). P4HA2 rescue reversed PLOD1 knockdown-mediated suppression of oncogenicity and pathway activation. The FAK inhibitor Y15 abrogated PLOD1-driven malignant phenotypes. In vivo, PLOD1 silencing inhibited tumour growth and reduced FAK/PI3K/AKT/mTOR phosphorylation. PLOD1 drives HNSCC progression by modulating P4HA2 and activating the FAK/PI3K/AKT/mTOR signalling cascade, positioning the PLOD1-P4HA2 axis as a promising prognostic biomarker and therapeutic target.