PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP

Proteasome activator 28γ (PA28γ) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as the main research model, and combining co-immunoprecipitation (Co-IP), proximity ligation assays (PLA), AlphaFold 3-based molecular docking, and truncation constructs, we discovered that PA28γ interacted with complement 1q binding protein (C1QBP). This interaction is dependent on the C1QBP N-terminus (aa 1-167) rather than the known functional domain. Point mutation in C1QBP (T76A/G78N) disrupting predicted hydrogen bonding with PA28γ-D177 significantly reduced their binding. Notably, we found that PA28γ enhances C1QBP protein stability in OSCC. Functionally, PA28γ and C1QBP co-localized in mitochondria, promoting fusion (via upregulation of OPA1, MFN1/2), respiratory complex expression, oxidative phosphorylation (OXPHOS), ATP production, and ROS generation. Crucially, PA28γ-enhanced OSCC cell migration, invasion, and proliferation in vitro were dependent on C1QBP. In vivo, orthotopic OSCC models showed Pa28γ overexpression increased tumor growth and elevated C1qbp levels, correlating with elevated ATP and ROS. Using transgenic Psme3^-/- mice and subcutaneous tumor grafts, we confirmed that silencing of Pa28γ suppresses tumor growth, reduces C1qbp levels, and dampens mitochondrial metabolism-specifically in knockout hosts. Clinically, PA28γ and C1QBP expression were positively correlated during oral carcinogenesis and in metastatic OSCC tissues across cohorts. High co-expression predicted poor prognosis in OSCC patients. Thus, PA28γ stabilizes C1QBP via N-terminal interaction to drive mitochondrial OXPHOS and tumor progression, highlighting its potential as a therapeutic target.