NPLOC4 (NPL4 homolog, ubiquitin recognition factor) functions as a critical component of the VCP-UFD1-NPLOC4 complex involved in protein quality control and cellular stress responses. The protein serves as an adaptor for the p97/VCP segregase, facilitating the turnover of proteins in multiple regulatory pathways 1. NPLOC4 is essential for endoplasmic reticulum-associated degradation (ERAD), where the VCP-UFD1-NPLOC4 complex binds ubiquitinated proteins and exports misfolded proteins from the ER to the cytoplasm for proteasomal degradation 2. The protein also plays important roles in autophagy regulation, where it interacts with the VCP-UFD1-NPLOC4 complex to promote p53 degradation and facilitate autophagy initiation 2. In aggresome clearance, NPLOC4 is required for the disintegration of protein aggregates, enabling their piecemeal autophagy through p97/VCP-mediated removal of ubiquitylated clients 3. Clinically, NPLOC4 has emerged as a potential therapeutic target, with studies showing its involvement in cancer progression and heart failure. The protein is upregulated in various tumors and correlates with poor prognosis, while its knockdown demonstrates protective effects in heart failure models by reducing oxidative stress and improving mitochondrial function 45. These findings establish NPLOC4 as a key regulator of proteostasis with significant therapeutic potential.