ArticleBiochemical genetics2026
The Sonic Hedgehog Pathway is Activated in Cushing's Disease with USP8 Mutations.
Article in Biochemical genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cushing's disease (CD) is a neuroendocrine disorder characterized by excessive adrenocorticotropic hormone (ACTH) secretion from pituitary adenomas, closely associated with ubiquitin-specific protease 8 (USP8) mutations. This study aimed to investigate whether USP8 mutations activate the Sonic Hedgehog (SHH) pathway by deubiquitinating its key component Smoothened (SMO), thereby promoting ACTH production in CD. mRNA expression profiles of USP8-mutated and wild-type CD patients (GEO dataset GSE132982) were analyzed for differentially expressed genes, followed by GO and KEGG pathway enrichment. USP8 mutant/wild-type plasmids were transfected into HeLa cells. Co-immunoprecipitation and Western blot evaluated USP8-SMO interaction and SMO ubiquitination. RT-qPCR, luciferase reporter assays, and nuclear translocation analysis assessed SHH pathway gene expression and GLI2 transcriptional activity. Immunohistochemistry detected SMO/SHH proteins in 9 USP8-mutated and 9 wild-type pituitary adenomas. Primary tumor cells were treated with the SMO inhibitor cyclopamine, and POMC mRNA/ACTH secretion were measured by RT-qPCR/ELISA. Chromatin immunoprecipitation (ChIP) verified GLI2 binding to the POMC promoter. SHH pathway genes were significantly dysregulated in USP8-mutated CD. Mutant USP8 enhanced SMO interaction, reduced SMO ubiquitination, and upregulated SHH target genes, promoting GLI2 nuclear translocation/activity. SMO-positive cells were more frequent in mutated tumors, with unchanged SHH expression. Cyclopamine suppressed POMC/ACTH specifically in mutated cells, and ChIP confirmed GLI2-POMC promoter binding. USP8 mutations activate the SHH pathway via SMO deubiquitination, driving GLI2-mediated POMC transcription and excessive ACTH secretion in CD. Targeting the SHH pathway may offer a novel therapeutic strategy for USP8-mutated Cushing's disease.
Indexed as
Identifiers
42101757What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.