TRIP4 (thyroid hormone receptor interactor 4) is a transcriptional coactivator that assembles into multi-protein complexes to regulate nuclear receptor-mediated gene expression. The protein binds directly to thyroid hormone receptor, estrogen receptor, and androgen receptor, as well as to coactivators including EP300, CREBBP, and NCOA1, and basal transcription factors TBP and TFIIA, facilitating their coordinated transactivation. Beyond nuclear receptors, TRIP4 plays a pivotal role in transactivating NF-κB, SRF, and AP-1, and mediates transrepression between nuclear receptors and either AP-1 or NF-κB 1. Recent structural evidence shows that the ASCH domain of TRIP4 binds DNA in a sequence-independent manner at the 5' and 3' ends 2. TRIP4 also functions within the RQC trigger (RQT) complex, which activates the ribosome quality control pathway to degrade problematic nascent peptides. Clinically, biallelic TRIP4 loss-of-function variants cause a congenital syndrome characterized by neonatal hypotonia, respiratory distress, joint hyperlaxity, and developmental delay 3. TRIP4 variants are associated with Alzheimer disease risk 4, and elevated TRIP4 expression promotes cervical cancer progression through GATA2 transactivation 5. In hepatocellular carcinoma, the MED8-TRIP4 axis drives sorafenib resistance, suggesting that targeting this pathway may enhance chemotherapy sensitivity.