FBXO21 (F-box protein 21) is a member of the F-box protein family and serves as the substrate recognition component of the SCF (Skp1-Cullin-F-box) E3 ubiquitin ligase complex. In AML cells, FBXO21 can ubiquitinate p85α, a regulatory subunit of the PI3K pathway, leading to its degradation. This reduces PI3K signaling, promotes p85α dimerization, and activates ERK, thereby influencing cell proliferation and survival. Silencing FBXO21 in AML cells induces differentiation, inhibits tumor progression, and increases sensitivity to chemotherapeutic agents. FBXO21 can regulate immune responses by ubiquitinating and degrading proteins like ASK1 through pro-inflammatory cytokine pathways. It can also ubiquitinate p85α, affecting CXCL10 expression and modulating immune cell infiltration and anti-tumor activity. In renal cell carcinoma, overexpression of FBXO21 significantly suppresses ccRCC cell proliferation and metastasis both in vitro and in vivo. It may be related to the stromal score and the infiltration levels of immune cells associated with prognosis. Additionally, FBXO21 overexpression increases the expression of key molecules in the CREB pathway.