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GeneE
10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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FBXO42
F-box protein 42
Chromosome 1 · 1p36.13
NCBI Gene: 54455Ensembl: ENSG00000037637.12HGNC: HGNC:29249UniProt: Q6P3S6
40PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
FUNCTIONAL ROLE
Highly Constrained
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindingubiquitin-like ligase-substrate adaptor activitySCF ubiquitin ligase complexSCF-dependent proteasomal ubiquitin-dependent protein catabolic processneurodegenerative diseaselysosomal storage diseasechronic obstructive pulmonary diseasearthritis
✦AI Summary

FBXO42 (F-box protein 42) functions as a substrate-recognition component of SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complexes, directing multiple protein targets for ubiquitination and degradation 1. FBXO42 recognizes diverse substrates including ACAA2 in hepatic lipid metabolism 1, SUMO1 in cancer cells 2, mutant p53 variants 3, Ataxin-2 during endoplasmic reticulum stress 4, p57Kip2 in hepatocellular carcinoma 5, and RBPJ in Notch signaling 6. The protein also regulates chr1-microtubule dynamics critical for mitotic checkpoint control in cancer cells 7. Mechanistically, FBXO42-mediated ubiquitination can proceed via lysine-63 linkage for non-degradative signaling functions or proteasomal degradation pathways 6. Disease relevance spans hepatocellular carcinoma, where FBXO42 overexpression drives progression through p57Kip2 degradation 5, glioblastoma stemness 7, Notch-driven leukemia 6, and potentially Parkinson's disease susceptibility 8. FBXO42 represents a therapeutic target, with small-molecule degraders activating FBXO42 showing anticancer efficacy against multiple tumor types 2, while FBXO42 inhibition may benefit NAFLD and certain leukemias 16.

Sources cited
1
FBXO42 is a component of Cullin1-based E3 ligase complex that promotes ACAA2 ubiquitination and degradation in hepatocytes, with relevance to NAFLD pathogenesis
PMID: 37528093
2
FBXO42 is the substrate receptor for CUL1 E3 ligase required for HB007-mediated SUMO1 ubiquitination and degradation with anticancer activity
PMID: 34644148
3
FBXO42 positively regulates p53 mutant stability in collaboration with CCDC6, controlling USP28-mediated mutant p53 stabilization
PMID: 38580884
4
FBXO42 promotes Ataxin-2 ubiquitination and degradation in granules, triggering terminal Xbp1 translation during ER stress-induced cell death
PMID: 40804044
5
FBXO42 promotes hepatocellular carcinoma progression by mediating p57Kip2 ubiquitination and degradation, with YY1 upregulating FBXO42 expression
PMID: 40842039
6
FBXO42 is essential in glioblastoma stem cells and other cancers, regulating chromosome-microtubule dynamics and spindle assembly checkpoint control independent of previously proposed targets
PMID: 38774470
7
FBXO42 gene haplotype associated with increased Parkinson's disease susceptibility in Chinese Han population
PMID: 24063688
8
FBXO42 promotes K63-linked polyubiquitination of RBPJ to enhance Notch signaling and chromatin relaxation, with therapeutic relevance to Notch-driven leukemia
PMID: 36129980
Disease Associationsⓘ20
neurodegenerative diseaseOpen Targets
0.55Moderate
lysosomal storage diseaseOpen Targets
0.36Weak
chronic obstructive pulmonary diseaseOpen Targets
0.26Weak
arthritisOpen Targets
0.26Weak
aneurysmOpen Targets
0.24Weak
smoking initiationOpen Targets
0.22Weak
muscular diseaseOpen Targets
0.13Weak
breast cancerOpen Targets
0.09Suggestive
hepatocellular carcinomaOpen Targets
0.08Suggestive
leukemiaOpen Targets
0.06Suggestive
neoplasmOpen Targets
0.05Suggestive
Familial progressive cardiac conduction defectOpen Targets
0.04Suggestive
Parkinson diseaseOpen Targets
0.04Suggestive
Arrhythmogenic right ventricular dysplasiaOpen Targets
0.04Suggestive
arrhythmogenic right ventricular dysplasia 10Open Targets
0.04Suggestive
Hemolytic anemia due to red cell pyruvate kinase deficiencyOpen Targets
0.03Suggestive
neuroblastomaOpen Targets
0.03Suggestive
Romano-Ward syndromeOpen Targets
0.03Suggestive
hemolytic anemia due to erythrocyte adenosine deaminase overproductionOpen Targets
0.03Suggestive
Brugada syndromeOpen Targets
0.03Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
FBXO48Shared pathway100%FBXO47Shared pathway100%FBXW12Shared pathway100%FBXO15Shared pathway100%AMN1Shared pathway100%FBXO39Shared pathway100%
Tissue Expression6 tissues
Heart
100%
Ovary
97%
Brain
90%
Lung
89%
Bone Marrow
70%
Liver
67%
Gene Interaction Network
Click a node to explore
FBXO42FBXO48FBXO47FBXW12FBXO15AMN1FBXO39
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted · UniProt Q6P3S6
View on AlphaFold ↗
Constraintⓘ
LOEUFⓘ
0.27Highly Constrained
pLIⓘ
1.00Intolerant
Observed/Expected LoF0.16 [0.10–0.27]
RankingsWhere FBXO42 stands among ~20K protein-coding genes
  • #10,171of 20,598
    Most Researched40
  • #920of 17,882
    Most Constrained (LOEUF)0.27 · top 10%
Genes detectedFBXO42
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2.
PMID: 37528093
Nat Commun · 2023
1.00
2
Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors.
PMID: 34644148
Sci Transl Med · 2021
0.90
3
Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.
PMID: 38580884
Mol Syst Biol · 2024
0.80
4
Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling.
PMID: 40804044
Nat Commun · 2025
0.70
5
FBXO42 promotes hepatocellular carcinoma progression via mediating p57Kip2 ubiquitination and degradation.
PMID: 40842039
Eur J Med Res · 2025
0.60