REDD1 in Clear Cell Renal Cell Carcinoma: Linking Stress Adaptation, Proteostasis and Therapeutic Resistance

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of RCC and is defined by loss of von Hippel-Lindau (VHL) function and dysregulated hypoxia signaling. Hyperactivation of the mTOR pathway is also frequently observed. These factors increase anabolic and protein-synthetic demand leading to proteotoxic stress. To survive under these conditions, ccRCC cells rely on adaptive endoplasmic reticulum (ER) stress responses and autophagy to maintain proteostasis. Regulated in Development and DNA Damage Response 1 (REDD1, also known as DDIT4) is a key stress response protein that integrates hypoxic, metabolic, and ER stress signals to regulate mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) activity and redox homeostasis. REDD1 can either suppress tumor growth through mTOR inhibition or promote survival by facilitating oxidative stress tolerance and autophagy depending on the specific context. In ccRCC, REDD1 expression is driven by VHL loss and HIF stabilization. Yet, mTORC1 activity frequently persists due to dysregulation of upstream repressors such as TSC1/TSC2, direct activating mutations in mTOR, and enhanced growth factor signaling. This paradox underscores the complex interplay between REDD1 and the oncogenic signaling landscape of RCC. Here, we review emerging evidence positioning REDD1 as a pivotal link between hypoxia, mTOR signaling, and ER stress in ccRCC and discuss how therapeutic modulation of this pathway through ER stress inducers, proteasome inhibitors, and p97/valosin-containing protein (VCP) inhibitors may overcome adaptive resistance and improve patient outcomes.