WAC (WW domain containing adaptor with coiled-coil) is a multifunctional regulatory protein that bridges transcriptional and post-translational processes. Structurally, WAC contains a WW domain that interacts with RNA polymerase II transcriptional machinery and a coiled-coil region that binds the RNF20-RNF40 ubiquitin ligase complex, thereby coupling histone H2B monoubiquitination at lysine 120 to active gene transcription 1. Beyond transcriptional regulation, WAC functions as a metabolic checkpoint protein that positively regulates mTORC1 signaling by promoting assembly of the TTT-RUVBL complex in an energy-dependent manner, while also acting as a selective autophagy regulator—promoting amino acid starvation-induced autophagy while suppressing basal autophagy 23. Recently, WAC was shown to facilitate mesenchymal stem cell osteogenesis by protecting PINK1 from ubiquitination-dependent degradation, thereby activating mitophagy and promoting new bone formation, with reduced WAC levels observed in osteoporosis patients 4. WAC regulates DNA damage checkpoint responses 1 and may negatively regulate proteasomal protein degradation. Pathologically, de novo mutations in WAC have been identified in moderate-to-severe intellectual disability cases 5, and WAC-AS1, its antisense RNA, shows aberrant expression correlating with immune infiltration and poor prognosis across multiple cancer types 6.