RARE DISEASE
Cushing disease
Cushing disease
Cushing disease
Synonyms: Corticotroph pituitary adenoma, Pituitary corticotroph micro-adenoma, Pituitary-dependent Cushing syndrome
Synonyms: Corticotroph pituitary adenoma, Pituitary corticotroph micro-adenoma, Pituitary-dependent Cushing syndrome
Synonyms: Corticotroph pituitary adenoma, Pituitary corticotroph micro-adenoma, Pituitary-dependent Cushing syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Cushing disease is an ACTH-dependent form of Cushing syndrome caused by a pituitary corticotroph adenoma, resulting in chronic hypercortisolism. It presents with central obesity, moon face, hypertension, glucose intolerance, proximal muscle weakness, and neuropsychiatric symptoms [4][5][14]. Diagnosis requires biochemical confirmation of hypercortisolism and pituitary MRI/ACTH testing [1][5]. First-line treatment involves transsphenoidal adenomectomy, with adjuvant therapies for persistent cases [1][4][15].
Categories: rare endocrine diseases, rare infertility disorders, rare neoplastic diseases
Research Papers
1,173 drug discovery papers related to Cushing disease, with 4 first-in-class and 18 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
1,173 drug discovery papers related to Cushing disease, with 4 first-in-class and 18 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-30 | Comparative analysis of neuropsychological impairments between Cushing's disease and non-functioning pituitary adenoma patients: the roles of HPA axis hormones and inflammatory markers in a prospective cohort study.
This prospective cohort study systematically compared neuropsychological impairments in Cushing's disease (CD),non-functioning pituitary adenomas (NFPA), and healthy controls (HCs), and investigated the roles of HPA axis hormones (ACTH, cortisol)and inflammatory markers in cognitive dysfunction. A total of 107 CD patients, 110 NFPA patients, and 84 HCs were enrolled from the Chinese PLA General Hospital.Participants underwent preoperative comprehensive neuropsychological assessments, including the Mini-Mental State Examination(MMSE) and Montreal Cognitive Assessment (MoCA), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), PittsburghSleep Quality Index (PSQI), and Quality of Life (QOL) Scale. Clinical data were also collected. Longitudinal neuropsychological changeswere evaluated in 90 CD patients post-surgery. Statistical analyses included FDR-corrected group comparisons, correlation analyses,and multivariable regression. Cushing's disease patients exhibited significantly greater deficits in global cognition (MMSE/MoCA, q < 0.001), depression/anxiety (SDS/SAS, q < 0.006), and quality of life compared with NFPA and HCs. Critically, morning ACTH levels (8 A.M.) predicted cognitive decline, whereas cortisol showed no significant correlation. Paradoxically, inflammatory markers (WBC, neutrophils, lymphocytes) positively correlated with MMSE scores (q < 0.024), suggesting compensatory neuroprotection, which needs further investigation. Postoperatively, significant improvements occurred in affective symptoms and cognition, with maximal recovery in memory and attention. The CD-specific neuropsychological impairments exceed tumor mass effects in NFPA, driven by HPA hyperactivation. ElevatedACTH is an associated predictor of cognitive decline, advocating for its prioritization in clinical monitoring. Surgical remission partiallyreverses deficits, while neuroendocrine-immune crosstalk bidirectionally modulates cognition. Adrenocorticotropic hormone-centricmanagement and targeted rehabilitation may optimize long-term outcomes.
2026-06-23 | A MYCN–GAL–SREBP1 Lipogenic Axis Drives Proliferation in Silent Corticotroph Adenomas
BACKGROUND: Silent corticotroph adenomas (SCAs) are an aggressive pituitary neuroendocrine tumor (PitNET) subtype lacking effective medical therapies and showing a high rate of recurrence. The molecular mechanisms driving their proliferation remain poorly understood. Although metabolic reprogramming is a hallmark of cancer, neither lipid metabolism nor its regulatory pathways have been systematically investigated in SCAs. METHODS: We performed integrative analyses of bulk and single-cell RNA sequencing datasets from SCAs, functioning corticotroph adenomas (FCAs), and normal pituitary tissue to characterize GAL expression and associated signaling pathways. Mechanistic studies employed GAL gain- and loss-of-function models, RNA sequencing, luciferase reporter assays, lipidomics, and pharmacological inhibition. Regulation of GAL by MYCN was assessed through promoter transactivation assays. The therapeutic efficacy of SREBP1 inhibition (fatostatin) was evaluated both in vitro and in vivo. RESULTS: We identified a marked downregulation of galanin (GAL) in SCAs and demonstrated that GAL loss promotes tumor cell proliferation. GAL deficiency activated the PI3K-Akt-mTOR signaling cascade, resulting in increased activity of SREBP1, a key transcriptional regulator of lipogenesis. Enhanced fatty-acid synthesis provided metabolic support for SCA growth. We further uncovered a linear regulatory axis in which MYCN directly upregulates GAL; however, MYCN downregulation in SCAs suppresses GAL expression, thereby enabling SREBP1-driven lipogenesis. Pharmacological inhibition of SREBP1 with fatostatin reduced lipogenesis and significantly suppressed SCA growth in vitro and in vivo. CONCLUSIONS: Our findings reveal a previously unrecognized MYCN-GAL-SREBP1 lipogenic axis that drives SCA proliferation. SREBP1-dependent lipogenesis represents a promising and druggable therapeutic vulnerability for the treatment of SCAs.
2026-06-16 | Structure-based rational design of high-affinity JAZF1 variants peptides to target the testicular orphan nuclear receptor 4 and pro-opiomelanocortin axis in Cushing's disease.
The regulation of pro-opiomelanocortin (Pomc) expression by the testicular orphan receptor 4 (TR4) constitutes a critical mechanism underlying the pathogenesis of Cushing's disease (CD). Although the endogenous repressor juxtaposed with another zinc finger gene 1 (JAZF1) inhibits TR4 activity, its relatively low binding affinity (KD = 2246 nM) limits its therapeutic potential. In this study, we employed an iterative structure-based lead optimization strategy to enhance the JAZF1 scaffold. Utilizing Discovery Studio for virtual screening, we conducted successive rounds of in silico saturation mutagenesis, ranging from single point to multi-site combinatorial substitutions, which were subsequently validated through incremental experimental binding assays. This recursive optimization process led to the identification of two triple-mutant JAZF1 peptides (V56L/A68Y/A69R and D67L/A68Y/A69R) exhibiting more than a 2,200-fold enhancement in TR4 binding affinity. These engineered peptides, along with high-affinity small molecules such as nilotinib (KD = 4.83 nM), effectively downregulated Pomc expression and inhibited proliferation of AtT-20 tumor cells. Taken together, these findings suggest that the JAZF1-TR4-Pomc axis may serve as a potential therapeutic target for modulating adrenocorticotropic hormone (ACTH) hypersecretion in CD.
2026-06-30 | Comparative analysis of neuropsychological impairments between Cushing's disease and non-functioning pituitary adenoma patients: the roles of HPA axis hormones and inflammatory markers in a prospective cohort study.
This prospective cohort study systematically compared neuropsychological impairments in Cushing's disease (CD),non-functioning pituitary adenomas (NFPA), and healthy controls (HCs), and investigated the roles of HPA axis hormones (ACTH, cortisol)and inflammatory markers in cognitive dysfunction. A total of 107 CD patients, 110 NFPA patients, and 84 HCs were enrolled from the Chinese PLA General Hospital.Participants underwent preoperative comprehensive neuropsychological assessments, including the Mini-Mental State Examination(MMSE) and Montreal Cognitive Assessment (MoCA), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), PittsburghSleep Quality Index (PSQI), and Quality of Life (QOL) Scale. Clinical data were also collected. Longitudinal neuropsychological changeswere evaluated in 90 CD patients post-surgery. Statistical analyses included FDR-corrected group comparisons, correlation analyses,and multivariable regression. Cushing's disease patients exhibited significantly greater deficits in global cognition (MMSE/MoCA, q < 0.001), depression/anxiety (SDS/SAS, q < 0.006), and quality of life compared with NFPA and HCs. Critically, morning ACTH levels (8 A.M.) predicted cognitive decline, whereas cortisol showed no significant correlation. Paradoxically, inflammatory markers (WBC, neutrophils, lymphocytes) positively correlated with MMSE scores (q < 0.024), suggesting compensatory neuroprotection, which needs further investigation. Postoperatively, significant improvements occurred in affective symptoms and cognition, with maximal recovery in memory and attention. The CD-specific neuropsychological impairments exceed tumor mass effects in NFPA, driven by HPA hyperactivation. ElevatedACTH is an associated predictor of cognitive decline, advocating for its prioritization in clinical monitoring. Surgical remission partiallyreverses deficits, while neuroendocrine-immune crosstalk bidirectionally modulates cognition. Adrenocorticotropic hormone-centricmanagement and targeted rehabilitation may optimize long-term outcomes.
2026-06-23 | A MYCN–GAL–SREBP1 Lipogenic Axis Drives Proliferation in Silent Corticotroph Adenomas
BACKGROUND: Silent corticotroph adenomas (SCAs) are an aggressive pituitary neuroendocrine tumor (PitNET) subtype lacking effective medical therapies and showing a high rate of recurrence. The molecular mechanisms driving their proliferation remain poorly understood. Although metabolic reprogramming is a hallmark of cancer, neither lipid metabolism nor its regulatory pathways have been systematically investigated in SCAs. METHODS: We performed integrative analyses of bulk and single-cell RNA sequencing datasets from SCAs, functioning corticotroph adenomas (FCAs), and normal pituitary tissue to characterize GAL expression and associated signaling pathways. Mechanistic studies employed GAL gain- and loss-of-function models, RNA sequencing, luciferase reporter assays, lipidomics, and pharmacological inhibition. Regulation of GAL by MYCN was assessed through promoter transactivation assays. The therapeutic efficacy of SREBP1 inhibition (fatostatin) was evaluated both in vitro and in vivo. RESULTS: We identified a marked downregulation of galanin (GAL) in SCAs and demonstrated that GAL loss promotes tumor cell proliferation. GAL deficiency activated the PI3K-Akt-mTOR signaling cascade, resulting in increased activity of SREBP1, a key transcriptional regulator of lipogenesis. Enhanced fatty-acid synthesis provided metabolic support for SCA growth. We further uncovered a linear regulatory axis in which MYCN directly upregulates GAL; however, MYCN downregulation in SCAs suppresses GAL expression, thereby enabling SREBP1-driven lipogenesis. Pharmacological inhibition of SREBP1 with fatostatin reduced lipogenesis and significantly suppressed SCA growth in vitro and in vivo. CONCLUSIONS: Our findings reveal a previously unrecognized MYCN-GAL-SREBP1 lipogenic axis that drives SCA proliferation. SREBP1-dependent lipogenesis represents a promising and druggable therapeutic vulnerability for the treatment of SCAs.
2026-06-16 | Structure-based rational design of high-affinity JAZF1 variants peptides to target the testicular orphan nuclear receptor 4 and pro-opiomelanocortin axis in Cushing's disease.
The regulation of pro-opiomelanocortin (Pomc) expression by the testicular orphan receptor 4 (TR4) constitutes a critical mechanism underlying the pathogenesis of Cushing's disease (CD). Although the endogenous repressor juxtaposed with another zinc finger gene 1 (JAZF1) inhibits TR4 activity, its relatively low binding affinity (KD = 2246 nM) limits its therapeutic potential. In this study, we employed an iterative structure-based lead optimization strategy to enhance the JAZF1 scaffold. Utilizing Discovery Studio for virtual screening, we conducted successive rounds of in silico saturation mutagenesis, ranging from single point to multi-site combinatorial substitutions, which were subsequently validated through incremental experimental binding assays. This recursive optimization process led to the identification of two triple-mutant JAZF1 peptides (V56L/A68Y/A69R and D67L/A68Y/A69R) exhibiting more than a 2,200-fold enhancement in TR4 binding affinity. These engineered peptides, along with high-affinity small molecules such as nilotinib (KD = 4.83 nM), effectively downregulated Pomc expression and inhibited proliferation of AtT-20 tumor cells. Taken together, these findings suggest that the JAZF1-TR4-Pomc axis may serve as a potential therapeutic target for modulating adrenocorticotropic hormone (ACTH) hypersecretion in CD.
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Drug Discovery Landscape
2 orphan drug designations for Cushing disease, including 2 approved therapies.
2 orphan drug designations for Cushing disease, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
osilodrostat [Isturisa] | small molecules | FDA | 2013-09-13 | 2020-03-06 | Recordati Rare Diseases, Inc |
pasireotide [Signifor] | small molecules | FDA | 2009-07-24 | 2012-12-14 | Novartis Pharmaceuticals Corporation |
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