FGF9 drives mitochondrial biogenesis in glioblastoma by activating the CREB-PGC-1α axis

  • Peptides. 2026 Jan:195:171463. doi: 10.1016/j.peptides.2025.171463.
Kun Xue  1 ,  Junmei Yang  2 ,  Jia Hu  1 ,  Lingwei Kong  1 ,  Xinguo Cui  1 ,  Yang Kong  3
Affiliations
  • 1. Department of Neurosurgery, Yantaishan Hospital, Yantai City, Shandong Province 264001, China.
  • 2. Department of Operating Room, Yantaishan Hospital, Yantai City, Shandong Province 264001, China.
  • 3. Intensive Care Unit-Laishan, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province 264000, China. Electronic address: [email protected].
PMID: 41485715 DOI: 10.1016/j.peptides.2025.171463
Abstract

Background: Mitochondrial biogenesis is upregulated in glioblastoma to support tumor growth, invasion, and chemoresistance by meeting the heightened metabolic demands of Cancer cells. Fibroblast Growth Factor 9 (FGF9) is a potent oncogenic driver in various cancers, promoting proliferation, survival, and angiogenesis. However, its role in regulating Mitochondrial Metabolism in glioblastoma remains unclear.

Methods: The activation of FGF9/Fibroblast Growth Factor receptor 2 (FGFR2) signaling and expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) were examined in clinical glioblastoma samples and cell lines using Real-Time PCR, immunohistochemistry, and western blotting. Mitochondrial biogenesis and function in FGF9-treated U-87 cells were evaluated by measuring relative mtDNA/nDNA ratio, mitochondrial mass (MitoTracker), complex activity, membrane potential, and ATP production. The role of cAMP response element-binding protein (CREB) signaling was investigated using the specific inhibitor H89.

Results: We found activated FGF9/FGFR2 signaling in glioblastoma patients, with elevated serum FGF9 and tumor FGFR2. PGC-1α was upregulated in samples and cell lines. FGF9 boosted mitochondrial biogenesis and function in U-87 cells, increasing mtDNA, mass, complex activity, membrane potential, and ATP production. Mechanistically, FGF9 promoted the expression of PGC-1α and mitochondrial transcription factor A (TFAM) via activation of CREB signaling. Inhibition of CREB phosphorylation by H89 abolished FGF9-induced upregulation of PGC-1α/TFAM, mtDNA replication, and ATP production.

Conclusion: These findings reveal that FGF9 enhances mitochondrial biogenesis in glioblastoma through the CREB-PGC-1α-TFAM axis, uncovering a novel metabolic mechanism underlying its pro-tumorigenic effects.

Keywords
CREB; FGF9; Glioblastoma; Mitochondrial biogenesis; PGC-1α.
Products