The ubiquitin-proteasome system (UPS) plays a critical role in cancer by regulating the degradation of key proteins involved in cell cycle control, DNA repair, apoptosis, and signaling pathways, making it a crucial mechanism for maintaining cellular homeostasis and preventing tumor development and progression. The expression levels of F-box ubiquitin E3 ligase, FBXO21, correlates with patient survival in several types of cancer, suggesting a role in tumorgenesis. We have previously shown silencing FBXO21 in acute myeloid leukemia (AML) cell lines and patient samples leads to differentiation, slowed tumor progression, increased chemotherapy sensitivity, and altered cytokine signaling. Further, we found that FBXO21 ubiquitinates p85Î±, a regulatory part of the phosphoinositide 3-kinase (PI3K) pathway, for degradation resulting in altered PI3K signaling. Although PI3K inhibitors are used in cancer treatment, issues like off-target effects, dose-limiting toxicities, and resistance necessitate further research and development for optimized efficiency and minimal negative effects in targeting the PI3K pathway. To further understand the role of FBXO21 in cancer, we utilized shRNAs targeting FBXO21 in various cancer cell lines to identify the role of FBXO21 in cellular proliferation, apoptosis, and alteration of the PI3K pathway. The PI3K signaling pathway is initiated through p85Î± binding to the catalytic subunit, p110, leading to downstream AKT and mTOR activation. We found knockdown of FBXO21 stabilizes p85Î±, leading to dimerization of free p85 and decreased PI3K pathway activation. Therefore, we hypothesize that FBXO21 may function as a novel regulator of PI3K signaling, offering an alternative approach to PI3K inhibitors. Our findings suggest that FBXO21 may represent a novel therapeutic target across various cancer subtypes to target the overactive PI3K pathway. Targeting FBXO21 may enhance the efficacy of current therapies and provide potential benefits for improving patient outcomes in the treatment of cancer, including but not limited to AML.