Fbxo21, a member of the F-box family proteins, is a subunit of the E3 ubiquitin ligase complex called SCFs (SKP1-Cullin-F-box). It plays a crucial role in regulating protein levels through ubiquitination and proteasomal degradation, thereby influencing multiple biological pathways. It has been implicated in cytokine-mediated signaling pathways, the PI3K pathway, and pathways related to autophagy and the epithelial-to-mesenchymal transition [1,2,3,4].

In acute myeloid leukemia (AML), silencing Fbxo21 in human-derived AML cell lines and primary patient samples led to differentiation, inhibited tumor progression, and sensitized cells to chemotherapy agents. This was due to Fbxo21-mediated degradation of p85α, a regulatory subunit of the PI3K pathway, which decreased PI3K signaling [1].

In osteoarthritis, Fbxo21 was upregulated in the cartilage of patients and in relevant animal models. In vivo and in vitro knockdown of Fbxo21 suppressed OA-related cartilage degeneration by activating autophagy, upregulating anabolism, alleviating apoptosis, and downregulating catabolism [2].

In gastric cancer, decreased Fbxo21 expression was associated with poor prognosis, and Fbxo21 inhibited cancer progression by inducing growth arrest and inhibiting migration and invasion through down-regulating Nr2f2 [3].

In hematopoiesis-specific Fbxo21 conditional knockout (cKO) mouse models, stressing the hematopoietic stem and progenitor cell (HSPC) populations with 5-fluorouracil injections resulted in decreased survival, indicating that Fbxo21 regulates HSPCs through cytokine-mediated pathways [4].

In summary, Fbxo21 is a key regulator in multiple biological processes. Studies using gene knockout models, especially the cKO mouse model, have revealed its significant roles in diseases such as AML, osteoarthritis, gastric cancer, and in hematopoiesis. Understanding Fbxo21's functions provides insights into disease mechanisms and potential therapeutic targets for these conditions.