WDR54 stabilizes the fatty acid transporter SLC43A3 via the deubiquitinase OTUB1 to drive HNSCC progression

Abstract Metabolic reprogramming drives head and neck squamous cell carcinoma (HNSCC), yet the underlying mechanisms remain elusive. Here, we identify WDR54 as a critical oncogenic driver. Clinical analyses reveal WDR54 is overexpressed in HNSCC and correlates with poor patient survival. Mechanistically, WDR54 interacts with the deubiquitinase OTUB1, enhancing its capacity to deubiquitinate and stabilize the fatty acid transporter SLC43A3. This prevents SLC43A3 proteasomal degradation, inducing lipid metabolic reprogramming essential for HNSCC proliferation and invasion. Furthermore, pharmacological intervention with dihydroergotamine effectively disrupts this WDR54-OTUB1-SLC43A3 axis, significantly suppressing HNSCC tumor growth in vivo. Collectively, our findings elucidate a previously unrecognized signaling axis integrating protein deubiquitination with lipid metabolism, highlighting dihydroergotamine as a promising targeted therapeutic strategy for HNSCC.