Abstract

Background Oral squamous cell carcinoma (OSCC) is a common oral cavity malignancy with a poor prognosis. Although chemokine-like receptor 1 (CMKLR1) has been implicated in tumor progression in several types of cancer, its role and underlying mechanisms in OSCC remain unclear. In this study, we examined the role and mitochondrial metabolism pattern of CMKLR1 in OSCC progression. Methods CMKLR1 expression was evaluated using data obtained from The Cancer Genome Atlas database and from immunohistochemical, RT-qPCR, and Western blotting analyses involving OSCC tissues and cell lines. Functional assays focusing on proliferation, migration, invasion, and colony formation were conducted after CMKLR1 knockdown or overexpression in OSCC cells. Proteomic analyses were conducted to identify CMKLR1-associated signaling pathways. Seahorse assays were used to assess mitochondrial oxidative phosphorylation (OXPHOS). In addition, the effect of mitochondrial inhibition with IACS-010759 was evaluated in CMKLR1-overexpressing models. Finally, signaling dependency was tested through PI3K/AKT inhibition and PGC-1α depletion. Results CMKLR1 expression was significantly elevated in OSCC, correlating with advanced OSCC, lymph node metastasis, and poor prognosis. CMKLR1 knockdown inhibited cell proliferation, migration, invasion, and epithelial‐to‐mesenchymal transition in vitro and suppressed tumor growth in vivo, whereas CMKLR1 overexpression had the opposite effect. Proteomic profiling and metabolic assays revealed that CMKLR1 knockdown suppressed mitochondrial function, decreased OXPHOS activity, and reduced ATP production. Additionally, pharmacological inhibition of OXPHOS with IACS-010759 significantly abrogated the tumor-promoting effects driven by CMKLR1 overexpression, thereby supporting a CMKLR1-OXPHOS regulatory axis in OSCC. Mechanistically, CMKLR1 activated PI3K/AKT signaling and induced PGC-1α production. Pharmacological blockade of PI3K/AKT abrogated CMKLR1-dependent PGC-1α