| Aspect | Key findings | Evidence type | Key citations with year and DOI URL |
|---|---|---|---|
| Identity/domains | FBXL8 matches the UniProt target Q96CD0: a human FBXL-family F-box protein with leucine-rich repeats (LRRs), consistent with an SCF substrate receptor architecture. Review-level structural analysis places FBXL proteins as substrate-recruiting subunits of SKP1-CUL1-RBX1 E3 ligases; Yao 2023 experimentally showed both the F-box and LRR regions are required for FBXL8-mediated p53 ubiquitination and degradation. (pqac-00000011, pqac-00000014) | Review, biochemical, cell | Mason and Laman 2020, Open Biology, https://doi.org/10.1098/rsob.200319; Yao et al. 2023, Clinical and Translational Medicine, https://doi.org/10.1002/ctm2.1208 |
| SCF complex role | FBXL8 functions as the substrate-recognition adaptor of an SCF E3 ubiquitin ligase. Breast-cancer and CRC studies support interaction with SCF components, while Yao 2023 showed full-length FBXL8, but not ΔFbox or ΔLRR mutants, supports p53 destabilization and oncogenic phenotypes. (pqac-00000006, pqac-00000014, pqac-00000015) | Biochemical, cell | Chang et al. 2020, medRxiv, https://doi.org/10.1101/2020.06.09.20127068; Yao et al. 2023, Clinical and Translational Medicine, https://doi.org/10.1002/ctm2.1208 |
| Validated substrates | Experimentally supported FBXL8-associated substrates or interactors include TP53 in CRC, unphosphorylated c-MYC, phospho-Thr283 cyclin D3, and Snail1 in cardiac fibroblasts. CCND2 and IRF5 were found in FBXL8-containing complexes in breast-cancer cells and increase upon FBXL8 knockdown, but evidence there is strongest for association or candidate degradation rather than full biochemical reconstitution. (pqac-00000005, pqac-00000000, pqac-00000007, pqac-00000008, pqac-00000002) | Biochemical, cell, in vivo | Yao et al. 2023, https://doi.org/10.1002/ctm2.1208; Bajpai et al. 2022, https://doi.org/10.1080/15384047.2022.2061279; Yoshida et al. 2021, https://doi.org/10.1038/s41388-020-01532-4; Li et al. 2024, https://doi.org/10.1038/s41419-024-06646-1; Chang et al. 2020, Cancers, https://doi.org/10.3390/cancers12082210 |
| Localization | Available evidence suggests FBXL8 is largely cytoplasmic in the c-MYC study, where loss of FBXL8 caused nuclear c-MYC accumulation, implying regulation of a cytoplasmic c-MYC pool. In heart, FBXL8 is enriched in cardiac fibroblasts and co-localizes with α-SMA-positive cells, with little signal in cardiomyocytes. (pqac-00000000, pqac-00000013) | Cell, imaging | Bajpai et al. 2022, https://doi.org/10.1080/15384047.2022.2061279; Li et al. 2024, https://doi.org/10.1038/s41419-024-06646-1 |
| Pathways | Current evidence links FBXL8 to p53 tumor-suppressor control in CRC, c-MYC proteostasis and G1-S progression, cyclin D3-Rb-Ki67 cell-cycle regulation in lymphoma, and Snail1-RhoA-α-SMA fibrotic signaling after MI. In breast cancer, FBXL8 also shapes a pro-tumor cytokine and chemokine milieu, connecting ubiquitin signaling to tumor microenvironment regulation. (pqac-00000005, pqac-00000000, pqac-00000009, pqac-00000008, pqac-00000002) | Biochemical, cell, in vivo | Yao et al. 2023, https://doi.org/10.1002/ctm2.1208; Bajpai et al. 2022, https://doi.org/10.1080/15384047.2022.2061279; Yoshida et al. 2021, https://doi.org/10.1038/s41388-020-01532-4; Li et al. 2024, https://doi.org/10.1038/s41419-024-06646-1; Chang et al. 2020, Cancers, https://doi.org/10.3390/cancers12082210 |
| Disease contexts | FBXL8 shows context-dependent disease associations: oncogenic in breast cancer and colorectal cancer, but tumor-suppressive in lymphoma models and anti-fibrotic after myocardial infarction. This makes FBXL8 notable as a context-dependent SCF adaptor rather than a uniformly oncogenic or suppressive factor. (pqac-00000002, pqac-00000005, pqac-00000009, pqac-00000008) | Cell, in vivo, clinical correlation | Chang et al. 2020, Cancers, https://doi.org/10.3390/cancers12082210; Yao et al. 2023, https://doi.org/10.1002/ctm2.1208; Yoshida et al. 2021, https://doi.org/10.1038/s41388-020-01532-4; Li et al. 2024, https://doi.org/10.1038/s41419-024-06646-1 |
| Quantitative findings/statistics | Breast cancer: FBXL8 mRNA was reported 23-fold higher in MCF7 and 15-fold in MDA-MB231 versus MCF10A; siRNA knockdown reached up to 95 percent, reduced viability by about 52.5 percent at 48 h, reduced proliferation 2 to 3-fold, increased early apoptosis to 20 percent and 24 percent, slowed migration by 14 percent and 40 percent, and reduced invasion 4 to 8-fold; patient-scale analyses included n = 1349 matched tissues and stage-associated increases with p < 0.01 to p < 0.001. CRC: 100 patients were analyzed, including 36 non-metastatic and 64 liver-metastatic cases; xenograft and metastasis studies used 12 nude mice total, 6 per group, with FBXL8 knockout reducing tumor burden and liver metastasis at p < 0.001. Cardiac fibrosis: rat heart time-course n = 5 and cardiac-fibroblast western quantitation n = 3; FBXL8 knockdown increased TGFβ-induced cardiac-fibroblast migration and proliferation by 1.4-fold and 1.3-fold, and RhoA-GTP rose 2.9-fold. Lymphoma: low-density assays used 1 × 10^4 cells, n = 4, with p = 0.02 and p < 0.01; xenografts used 2 × 10^6 CA46 cells in SCID mice, n = 10, with tumor-volume and tumor-weight reductions reported at p = 0.02, p = 0.02, p = 0.03, and p < 0.01. (pqac-00000006, pqac-00000002, pqac-00000005, pqac-00000015, pqac-00000013, pqac-00000009) | Cell, in vivo, clinical correlation | Chang et al. 2020, medRxiv, https://doi.org/10.1101/2020.06.09.20127068; Chang et al. 2020, Cancers, https://doi.org/10.3390/cancers12082210; Yao et al. 2023, https://doi.org/10.1002/ctm2.1208; Li et al. 2024, https://doi.org/10.1038/s41419-024-06646-1; Yoshida et al. 2021, https://doi.org/10.1038/s41388-020-01532-4 |
| Applications/therapeutic angle | No FBXL8-targeted therapy is established clinically, but the literature repeatedly frames FBXL8 as a potential therapeutic node: inhibition may be attractive in breast and colorectal cancer where FBXL8 promotes tumor traits, whereas augmentation or gene delivery may be beneficial after MI where AAV9-FBXL8 reduced fibrosis. Editorial commentary highlights ubiquitin-ligase adaptors such as FBXL8 as promising but underdeveloped therapeutic targets, including in targeted protein degradation strategies. (pqac-00000005, pqac-00000008, pqac-00000012) | Editorial, translational interpretation, in vivo | Vriend 2023, Cancers, https://doi.org/10.3390/cancers15133460; Yao et al. 2023, https://doi.org/10.1002/ctm2.1208; Li et al. 2024, https://doi.org/10.1038/s41419-024-06646-1 |


*Table: This table summarizes the main functional-annotation evidence for human FBXL8 or Q96CD0 across molecular function, substrates, localization, pathways, disease roles, and translational implications. It is useful as a compact evidence map that distinguishes validated findings from broader review and editorial interpretation.*