X-linked ubiquitin-specific peptidase 11 (USP11) increases susceptibility to Cushing's disease in women.

The incidence of pituitary adrenocorticotropic hormone (ACTH)-secreting PitNETs, commonly known as ACTH PitNETs, is significantly higher in females; however, the underlying causes for this gender disparity remain unclear. In this study, we analyzed the expression of deubiquitinating enzymes in functioning ACTH PitNETs from both male and female subjects using RNA sequencing and identified USP11 as a potential susceptibility factor contributing to the higher prevalence of these PitNETs in females. Further investigation revealed that USP11 expression is markedly elevated in female functioning ACTH PitNETs, with levels significantly higher than those observed in male PitNETs and normal pituitary tissue. Experimental data indicate that USP11 promotes the transcription of proopiomelanocortin (POMC) and the secretion of ACTH. In contrast, knockdown of USP11 leads to a substantial reduction in both POMC transcription and ACTH secretion, as demonstrated in both in vitro and in vivo models. Mechanistically, we found that USP11 facilitates the deubiquitination of the key transcription factor TPIT in functioning ACTH PitNETs, enhancing its protein stability and thereby promoting POMC transcription and ACTH secretion. Additionally, virtual screening identified Lomitapide and Nicergoline as potential inhibitors of USP11, reducing POMC expression and ACTH secretion. Thus, USP11 emerges as a potential therapeutic target, and drugs aimed at inhibiting its function could benefit women with Cushing's disease.