The Dual Role of TRADD in Liver Disease: From Cell Death Regulation to Inflammatory Microenvironment Remodeling.

The global burden of liver diseases continues to rise, encompassing diverse pathologies such as viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In recent years, TNFR1-associated death domain protein (TRADD), a pivotal adaptor molecule in the TNF signaling pathway, has been found to play a dual regulatory role in the pathogenesis of liver diseases. Through its death domain, TRADD binds to TNFR1 and dynamically recruits downstream factors (e.g., TRAF2, RIPK1, FADD) to form Complex I or IIa, thereby activating pro-survival or pro-apoptotic signals that dictate hepatocyte fate and modulate the inflammatory microenvironment. This review systematically summarizes the molecular structure and functional networks of TRADD, along with its mechanistic roles in liver diseases: in HCC, TRADD expression correlates with tumor differentiation and is regulated by miRNA targeting; in ALD and MASLD, TRADD-mediated apoptosis is closely linked to fibrotic progression; and in acute liver injury, TRADD signaling is modulated by factors such as HO-1 to mitigate damage. Furthermore, TRADD inhibitors and antisense oligonucleotides demonstrate therapeutic potential. This review highlights the clinical translational value of TRADD as a diagnostic, therapeutic, and prognostic biomarker for liver diseases, providing a theoretical foundation for future precision medicine strategies.