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Osteoarthritis (OA) is a heterogeneous disease that is extremely hard to cure owing to its complex regulation network of pathogenesis, especially cartilage degeneration. FBXO21 is a subunit of ubiquitin E3 ligases that degrades P‐glycoprotein and EID1 by ubiquitination and activates the JNK and p38 pathways; however, its role in OA remains unknown. Here, the main objective of this study was to evaluate the potential effects and mechanism of FBXO21 in OA degeneration, we revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate‐induced OA rats, and chondrocytes treated with interleukin‐1β, tumor necrosis factor‐α, and lipopolysaccharide. Moreover, the in vivo and in vitro knockdown of FBXO21 suppressed OA‐related cartilage degeneration, as evidenced by activated autophagy, upregulated anabolism, alleviated apoptosis, and downregulated catabolism. In contrast, its overexpression promoted OA‐related cartilage degeneration. In addition, using mass spectrometry and co‐immunoprecipitation assay, we demonstrated that the downstream mechanism of FBXO21 inhibits autophagy by interacting with and phosphorylating ERK. Furthermore, FBXO21 alleviated anabolism and enhanced apoptosis and catabolism by inhibiting autophagy in rat chondrocytes. Interestingly, for its upstream mechanism, JUNB promoted FBXO21 expression by directly targeting the FBXO21 promoter, thus further accelerating cartilage degeneration in SW1353 cells and rat chondrocytes. Overall, our findings reveal that the JUNB‐FBXO21‐ERK axis regulates OA apoptosis and cartilage matrix metabolism by inhibiting autophagy. Therefore, FBXO21 is an attractive target for regulating OA pathogenesis, and its knockdown may provide a novel targeted therapy for OA. FBXO21 is upregulated in osteoarthritis (OA). Knockdown and overexpression of FBXO21 suppresses and promotes OA‐related degeneration, respectively. Mechanistically, FBXO21 inhibits autophagy by interacting with and phosphorylating ERK, and enhances OA‐related degeneration by inhibiting autophagy. JUNB regulates FBXO21 expression via targeting FBXO21 promoter and accelerates OA‐related degeneration by promoting FBXO21.

F-box protein 21 (Fbxo21), a member of the F-box family proteins, constitutes one of the four subunits of an E3 ubiquitin ligase complex called SCFs (SKP1-Cullin-F-box). Despite the effect on antivirus immune response and ubiquitination regulation of a few oncoproteins, such as EID1 and P-gp, little is known about the Fbxo21 function in tumors, including gastric cancer. In our study, we confirmed that Fbxo21 expression was decreased in gastric cancer tissues. Decreased expression of Fbxo21 was significantly associated with poor prognosis in gastric cancer. Fbxo21 inhibited gastric cancer progression by inducing growth arrest and inhibiting migration and invasion. The expression of various EMT markers, such as E-cadherin, N-cadherin and Vimentin were altered after Fbxo21 knockdown or overexpression. Moreover, we demonstrated that Fbxo21 inhibited the EMT via the down-regulation of Nr2f2. Fbxo21 expression was negatively correlated with Nr2f2 protein expression in gastric cancer tissues and cell lines. And the Nr2f2 protein abundance was regulated by Fbxo21 via ubiquitination and proteasomal degradation. At last, we demonstrated the effects of Nr2f2 re-expression and inhibition on stable Fbxo21-overexpression or Fbxo21-silenced cell lines. These results suggested that Fbxo21 inhibited the proliferation and EMT in part through down-regulating the Nr2f2.

Background Numerous potential therapeutic alternatives for intervertebral disc degeneration (IDD) have been investigated, the most promising of which are based on biological variables such as microRNAs (miRNAs). Therefore, we verified the hypothesis that miRNAs modulate IDD by affecting the FBXO21-ERK signalling pathway. Methods Microarray and quantitative real-time polymerase chain reaction (RT–qPCR) tests were used to examine the expression profiles of miRNAs in nucleus pulposus (NP) cells between patients with IDD and controls. Western blotting and luciferase reporter assays were used to identify the miRNA targets. Results Microarray and RT–qPCR assays confirmed that the expression level of miR-217 was significantly decreased in degenerative NP cells. CpG islands were predicted in the miR-217 promoter region. The IDD group had considerably higher methylation than the control group. Gain- and loss-of-function experiments revealed that miR-217 mimics inhibited apoptosis and extracellular matrix (ECM) breakdown in NP cells. Bioinformatic analyses and luciferase assays were used to determine the connection between miR-217 and FBXO21. In vitro tests revealed that miR-217 mimics inhibited the expression of FBXO21, pERK, MMP13, and ADAMTS5 proteins, successfully protecting the ECM from degradation. Additionally, in vivo investigation using the IDD mouse model demonstrated that the miR-217 agonist may sufficiently promote NP cell proliferation, decrease apoptosis, promote ECM synthesis, and suppress the expression of matrix-degrading enzymes in NP cells. Conclusions Overexpression of miR-217 inhibits IDD via FBXO21/ERK regulation. Trial registration This study was performed in strict accordance with the NIH guidelines for the care and use of laboratory animals (NIH Publication No. 85-23 Rev. 1985) and was approved by the human research ethics committee of Wuhan University Renmin Hospital (Approval No. RMHREC-D-2020-391), and written informed consent was obtained from each participant.

Background Many studies have shown that F-box proteins regulate epithelial-mesenchymal transition, which is closely related to tumor metastasis. However, there is still limited research on the role of F-box proteins in renal cell carcinoma (RCC). Methods Public databases were used to screen differentially expressed genes among 37 F-box proteins in clear cell RCC (ccRCC). The expression of the differential gene FBXO21 and its prognostic value were verified by RT-qPCR and immunohistochemistry. Pyrosequencing was used to detect the regulatory effect of DNA methylation on FBXO21 expression. The effects of FBXO21 expression on cell proliferation and metastasis were clarified through cell phenotype experiments and animal models. The relationship between FBXO21 expression and the infiltration levels of tumor immune cells was also analyzed. GSEA and Western blot were used to identify the downstream molecular pathways associated with FBXO21 expression. Results Our results revealed that FBXO21 was significantly underexpressed in ccRCC and that increased FBXO21 expression predicted a better patient prognosis. The promoter region of FBXO21 exhibited DNA hypermethylation, and FBXO21 expression was significantly restored after demethylation. In addition, FBXO21 overexpression significantly inhibited the proliferation and metastasis of ccRCC cells both in vitro and in vivo. Mechanistically, FBXO21 expression was related to the stroma score and the infiltration levels of immune infiltrating cells associated with prognosis. Moreover, FBXO21 overexpression increased the expression of key molecules in the CREB pathway. Conclusions These results suggest that FBXO21 is a novel prognostic biomarker for ccRCC patients and functions as a tumor suppressor gene. Moreover, FBXO21 may regulate the CREB pathway and is closely related to tumor immune cell infiltration in ccRCC.

Osteoarthritis (OA) is a chronic degenerative joint disease and is the most prevalent and disabling form of arthritis worldwide. Autophagy plays a vital role in OA. This study aimed to explore whether covalently closed circular RNA MSR (circRNA‐MSR) could affect the F‐box Only Protein 21 (FBXO21) expression by targeting microRNA‐761 (miR‐761), thereby affecting the autophagy in OA chondrocytes. Clinical OA tissues were collected, and circRNA‐MSR, miR‐761, and FBXO21 expressions were detected via quantitative real‐time polymerase chain reaction (qRT‐PCR). An in vitro OA model was constructed by treating C28/I2 cells with LPS and treating them with overexpression or knockdown vector of circRNA‐MSR, miR‐761, and FBXO21, and autophagy inhibitor 3‐MA. Fluorescence in situ hybridization (FISH) determined the location of circRNA‐MSR and miR‐761. Dual‐luciferase assay assessed circRNA‐MSR and miR‐761, along with the bindings of miR‐761 and FBXO21. Cell viability was detected by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. LC3 II/I, p62 and beclin 1 expressions were detected via the western blot. circRNA‐MSR and FBXO21 levels were elevated in OA, but miR‐761 level was inhibited. Suppressing circRNA‐MSR promoted the autophagy of LPS‐treated cells. circRNA‐MSR could bind to miR‐761 and inhibit its expression. MiR‐761 inhibition reversed the promoted autophagy caused by circRNA‐MSR knockdown in LPS‐treated C28/I2 cells. Moreover, miR‐761 could target FBXO21 and inhibit its expression. FBXO21 overexpression reversed the increased autophagy caused by miR‐761 overexpression in LPS‐treated C28/I2 cells. circRNA‐MSR could affect FBXO21 level via targeting miR‐761, thereby repressing autophagy in OA chondrocytes, providing a new target and strategy for OA treatment.

Acute kidney injury (AKI) is a serious disease with a high incidence and easy induction. The search for innovative biomarkers and treatment methods is of great significance for improving the prognosis of patients. Autophagy is closely related to the occurrence and development of AKI. This study aims to explore the role of autophagy-related genes (ARGs) as potential biomarkers and therapeutic targets in AKI. In this study, the gene microarray data of the GEO dataset were used to explore the molecular profile of AKI, and three machine learning algorithms were used to screen autophagy-related feature genes. To further validate the reliability of the screening results, we constructed a cisplatin-induced AKI rat model to validate potential biomarkers of machine learning screening. Machine learning analysis identified 17 differentially expressed ARGs and selected the core genes FIZ1 and FBXO21, with area under curve (AUC) values both exceeding 0.7 (95% CI [0.706-0.899]). Immune analysis revealed that the number of Mast cells resting significantly decreased in AKI samples compared to normal samples (  < 0.05). Electron microscopy observations of the cisplatin-induced AKI rat model indicated thickening of the basement membrane, fusion of foot processes, and swelling and rupture of mitochondria in the model group, suggesting a correlation between AKI and mitochondrial autophagy; Western blot results indicated a significant increase in the expression of FIZ1 and a significant decrease in FBXO21 in the AKI group (  < 0.01). The results of IHC staining were also consistent with those of Western blot results. This study highlights the significant role of ARGs in AKI and identifies FIZ1 and FBXO21 as promising biomarkers with high diagnostic potential, offering new insights into the molecular mechanisms underlying AKI.

Protein ubiquitination regulated by ubiquitin ligases plays important roles in innate immunity. However, key regulators of ubiquitination during innate response and roles of new types of ubiquitination (apart from Lys48- and Lys63-linkage) in control of innate signaling have not been clearly understood. Here we report that F-box only protein Fbxo21, a functionally unknown component of SCF (Skp1–Cul1–F-box protein) complex, facilitates Lys29-linkage and activation of ASK1 (apoptosis signal-regulating kinase 1), and promotes type I interferon production upon viral infection. Fbxo21 deficiency in mice cells impairs virus-induced Lys29-linkage and activation of ASK1, attenuates c-Jun N-terminal kinase (JNK) and p38 signaling pathway, and decreases the production of proinflammatory cytokines and type I interferon, resulting in reduced antiviral innate response and enhanced virus replication. Therefore Fbxo21 is required for ASK1 activation via Lys29-linkage of ASK1 during antiviral innate response, providing mechanistic insights into non-proteolytic roles of SCF complex in innate immune response. The innate immune system is the body’s first line of defense against being infected by viruses and other microbes. Upon recognizing a virus, host cells trigger the innate immune response in an effort to eliminate the threat. However, innate immune responses must be carefully controlled because an excessive response can cause inflammation that harms the body. The innate immune response involves a variety of cells and processes that are each activated through a series of communication systems called signaling pathways. While much has been learned about which parts of a virus trigger the innate immune response, it is not clear how the immune response to the virus is controlled. It has been suggested that a process known as ubiquitination could be involved in regulating the activity of signaling pathways that activate the innate immune response. During ubiquitination, enzymes attach a small molecule called ubiquitin to a specific target protein. Ubiquitin often acts as a label that targets a particular protein for destruction. Enzymes called E3 ubiquitin ligases play central roles in identifying specific target proteins for ubiquitination. Some of these enzymes consist of a single protein unit that acts alone, but other E3 ubiquitin ligases are formed by groups (or “complexes”) of several proteins working together. Members of the F-box only protein family are components of some ubiquitin ligase complexes. Here, Yu et al. used a “microarray” technique to assess which F-box only proteins in mice are produced during an immune response to two viruses. The experiments identified an F-box protein called Fbxo21 as a potential candidate for a role in regulating the innate immune response. Additional experiments revealed that Fbxo21 is involved in adding ubiquitin to a specific location on a signaling protein called ASK1, which is known to be crucial for innate immune responses. Instead of targeting ASK1 for destruction, this ubiquitination activates ASK1. Therefore, Yu et al.’s findings demonstrate that Fbxo21 plays an important role in regulating innate immune responses. A future challenge is to investigate exactly how ASK1 is activated by the ubiquitin.