2. Academic Validation
  3. HTR1D regulates the PI3K/Akt signaling pathway to impact glioblastoma development and resistance to temozolomide

HTR1D regulates the PI3K/Akt signaling pathway to impact glioblastoma development and resistance to temozolomide

  • Chem Biol Interact. 2025 Sep 17:421:111748. doi: 10.1016/j.cbi.2025.111748.
Huanqi Zhang 1,  Ziyan Liu 2,  Jing Cheng 3,  Yiming Jiang 4,  Xiaoli Zheng 5,  Chong Zhang 6,  Yangling Li 7
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China; School of Medicine, Hangzhou City University, Hangzhou, 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
  • 3 School of Medicine, Hangzhou City University, Hangzhou, 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 4 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 5 School of Medicine, Hangzhou City University, Hangzhou, 310015, China; Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou City University, Hangzhou, 310058, China. Electronic address: geizxll@hotmail.com.
  • 6 School of Medicine, Hangzhou City University, Hangzhou, 310015, China; Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou City University, Hangzhou, 310058, China. Electronic address: zhangchong@hzcu.edu.cn.
  • 7 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China. Electronic address: liyangling1215@163.com.
PMID: 40972861 DOI: 10.1016/j.cbi.2025.111748
Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor, presents significant therapeutic challenges owing to limited treatment options beyond the cornerstone chemotherapy temozolomide (TMZ) and its intrinsic chemoresistance. This study elucidates additional mechanisms of the multimodal antidepressant vortioxetine in GBM, extending beyond the reported PI3K/Akt pathway modulation. RNA-sequencing analysis identified five potential vortioxetine-responsive targets in GBM cells: SCN5A, HTR1D, SLC6A9, KIF11, and ADRB2. Notably, only HTR1D overexpression correlated with poor disease-free survival in GBM patients. Vortioxetine-mediated HTR1D suppression suggests its potential role as an HTR1D inhibitor in GBM progression. HTR1D-overexpressing GBM cells exhibited enhanced proliferative and migratory capacities. LinkedOmics database analysis revealed the HTR1D regulation on PI3K/Akt axis, a dominant signaling pathway showing significant positive correlation with TMZ resistance. Crucially, HTR1D knockdown enhanced TMZ sensitivity in GBM cells. Moreover, the TMZ-vortioxetine combination demonstrated marked synergistic anti-tumor effects concomitant with HTR1D suppression. In vivo, the TMZ-vortioxetine combination more effectively suppressed GBM proliferation than either agent alone. Collectively, these findings identify HTR1D as a novel vortioxetine target in GBM that modulates proliferation, metastasis, and TMZ resistance via PI3K/Akt signaling. This study provides convincing preclinical evidence for TMZ-vortioxetine combination therapy, proposing both a new therapeutic target and a viable strategy to circumvent TMZ resistance in GBM.

Keywords

5-Hydroxytryptamine receptor 1D; Glioblastoma; PI3K/Akt; Temozolomide; Vortioxetine.

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