A MYCN–GAL–SREBP1 Lipogenic Axis Drives Proliferation in Silent Corticotroph Adenomas

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ID: 318415
2026
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Abstract
Abstract 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.
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Authors Changxi Han, Jianli Wu, Jing Xie, Li J, Zongze He, Bo Zhang, Yihan Dong, Qiuyue Fang, Jingwei Ye, Zhuoyi Tang, Can Xu, Jie Yang, Yue Wang, Mingjun Gao, Jin Zhang, Huan Xiong, Zhe Wu, Ruxiang Xu, Shaojian Lin
Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag141
URL
https://doi.org/10.1093/neuonc/noag141
Keywords Keywords not found

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