PHYHD1-mediated translational control regulates renal cell carcinoma progression.

The mechanisms underlying renal cell carcinoma (RCC) progression remain incompletely understood. Here, we identify phytanoyl-CoA dioxygenase domain containing 1 (PHYHD1) as a tumor suppressor that regulates translational homeostasis and RCC progression. Progressive PHYHD1 loss promotes tumor advancement and predicts poor prognosis, as revealed by integrative deep learning analysis of pan-cancer datasets. Restoring PHYHD1 suppresses tumor growth in RCC cell and patient-derived xenograft (PDX) models independently of its dioxygenase activity. Mechanistically, PHYHD1 interacts with translation elongation factor eEF1A1, alters its association with ribosomes, and restrains protein translation. Ribosome profiling and RNA-seq identify ceramide transporter 1 (CERT1) as a key effector of the PHYHD1-eEF1A1 axis. PHYHD1 depletion enhances CERT1 translation, whereas targeting CERT1 impairs proliferation of PHYHD1-deficient cells. These findings define a PHYHD1-eEF1A1-CERT1 axis that controls translation during RCC progression and highlight CERT1 as a potential therapeutic target in PHYHD1-deficient tumors.