Sruthi Sureshkumar

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.

Increased basal protein synthesis activity is a hallmark feature that distinguishes many types of malignant cells from their normal counterparts. The survival and proliferation of cancer cells are tightly linked to functional unfolded protein response (UPR) and endoplasmic reticulum (ER)-associated degradation (ERAD) pathways due to their high rates of protein synthesis. The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP)/p97 facilitates the extraction of proteins from organelles, chromatin, and protein complexes to target them for ubiquitin–proteasome system (UPS)-mediated degradation. p97 plays a key role in protein quality control and in the maintenance of protein homeostasis through its regulation of ERAD. The disruption of p97 activity leads to an accumulation of undegraded proteins, triggers the UPR, and can culminate in proteotoxic cell death. Given this, p97 inhibition offers an opportunity to selectively kill cancer cells that exhibit high basal protein synthesis rates. This review explores p97’s molecular structure, diverse cellular roles, and clinical potential with a particular focus on CB-5083 and CB-5339, the only p97 inhibitors to date that have advanced into clinical trials. We discuss their mechanisms of action, clinical trial outcomes, and the transformative potential of rational combination strategies to maximize their therapeutic potential. By integrating foundational biological insights with translational perspectives, we highlight p97 as a precision target for cancer treatment.

The NADPH oxidase 2 (NOX2) complex is a critical regulator of immune homeostasis. It is utilized by phagocytic leukocytes including neutrophils, monocytes, and macrophages to generate reactive oxygen species (ROS) that drive microbe clearance and modulate inflammatory responses. Within NOX2, the essential scaffold protein p47phox plays a pivotal role in orchestrating enzyme activation and facilitating the assembly and membrane translocation of cytosolic components of the complex. Tight regulation of p47phox activity is crucial, and its disruption is linked to a number of pathological conditions. Conversely, its hyperactivity contributes to oxidative stress, tissue damage, the progression of cardiovascular diseases, neurodegenerative disorders, inflammatory conditions, metabolic syndromes, and cancer. In this review, we detail the structural and functional roles of p47phox, mechanisms of its regulation, and its multifaceted contributions to disease pathogenesis. We explore the latest advances in p47phox-targeted therapeutic strategies, discuss current challenges in the field, highlight p47phox’s potential as a transformative target in redox biology and propose future directions to unlock its clinical utility.