Derl1-flox Mouse

Derl1, also known as derlin 1, is an important protein involved in the endoplasmic reticulum-associated degradation (ERAD) pathway. It participates in the retrotranslocation and degradation of misfolded proteins from the endoplasmic reticulum (ER), which is crucial for maintaining protein homeostasis within the cell [6].

Derl1 has been implicated in multiple diseases. In triple-negative breast cancer (TNBC), it is part of the VCP-TMEM63A-DERL1 signaling axis. Pharmacological inhibition of VCP or knockdown of DERL1 can partially abolish the oncogenic effects of TMEM63A on TNBC progression, suggesting its role in promoting TNBC cell proliferation, migration, and invasion [1]. In breast cancer, overexpression of DERL1 promotes p-AKT activation through K63 ubiquitination, and knockdown of DERL1 inhibits breast cancer cell growth both in vitro and in vivo [2]. In non-small-cell lung cancer, TEAD1 transcriptionally activates DERL1, and the circTTBK2/miR-873-5p/TEAD1/DERL1 axis is involved in tumorigenesis [3]. In oral squamous cell carcinoma (OSCC), DERL1 is involved in resistance to cisplatin-induced cell death, and melatonin can enhance cisplatin-induced cell death by inhibiting DERL1 [4]. In hepatocellular carcinoma (HCC), DERL1 promotes tumor progression via the AKT pathway, and its high expression is associated with larger tumor diameters and lymph node metastases [5]. In non-alcoholic fatty liver disease (NAFLD), Derlin-1 can both promote the disease by increasing RIPK3-mediated necroptosis [7] and ameliorate nonalcoholic hepatic steatosis by promoting ubiquitylation and degradation of FABP1 [9]. In pulmonary arterial hypertension, DERL1 is identified as one of the top 5 hub genes related to ER stress, and these hub genes are closely related to immune cells [8].

In conclusion, Derl1 plays essential roles in protein quality control through the ERAD pathway. Its dysregulation is associated with multiple diseases, including various cancers and metabolic diseases. Studies using knockdown or inhibition of Derl1 in different in vitro and in vivo models have revealed its oncogenic or disease-promoting roles, highlighting its potential as a therapeutic target for these diseases.