The CRIP1/NFATC2/SREBF1 axis drives melanoma progression by promoting reactive oxygen species-mediated endoplasmic reticulum stress activation

Malignant melanoma remains a formidable clinical challenge due to its propensity for metastasis and therapeutic resistance. Identifying molecular targets that regulate malignant melanoma progression is critical for developing effective therapies. In this study, we investigated the role of cysteine-rich intestinal protein 1 (CRIP1), a novel oncogene, in melanoma progression. CRIP1 expression was analyzed using public datasets, and functional roles of CRIP1 in proliferation, colony formation, migration, and invasion were assessed via overexpression cell models. Mechanistic insights were gained through RNA sequencing, bioinformatics, 4-phenylbutyric acid (4-PBA) or N-acetylcysteine (NAC) treatment, Western blot, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP). Xenograft models were used to confirm in vivo effects. CRIP1 was significantly upregulated in melanoma tissues, particularly in metastases, and correlated with an endoplasmic reticulum (ER) stress gene signature. CRIP1 overexpression promoted malignant phenotypes in vitro and tumor growth in vivo, which was dependent on the activation of ER stress. Integrative analysis identified SREBF1 (Sterol Regulatory Element Binding Transcription Factor 1) as a downstream target. CRIP1 increased intracellular ROS levels by promoting SREBF1 expression, thereby activating ER stress and promoting malignant phenotypes in melanoma cells. Mechanistically, CRIP1 promoted NFATC2 (nuclear factor of activated T cells 2) binding to the SREBF1 promoter to drive transcription of SREBF1. These findings indicate that CRIP1 serves as a critical driver of melanoma progression through ER stress activation and identify a novel CRIP1/NFATC2/SREBF1 axis, providing insights into the role of CRIP1 in melanoma biology and presenting new potential therapeutic targets for this aggressive malignancy.