2. Academic Validation
  3. PFKFB4-Mediated HSPB1 phosphorylation suppresses ferroptosis to Promote gastric cancer progression

PFKFB4-Mediated HSPB1 phosphorylation suppresses ferroptosis to Promote gastric cancer progression

  • Biochem Pharmacol. 2026 Apr:246:117714. doi: 10.1016/j.bcp.2026.117714.
Mengdi Ma 1,  Xin Xu 2,  Kexun Yu 2,  Xiongwei Yang 1,  Weidong Qiang 1,  Emre Dal 3,  Yonghong Zhang 2,  Jiangrun Zhu 4,  Ruochuan Sun 5,  Shangxin Zhang 6,  Yongxiang Li 7
Affiliations

Affiliations

  • 1 Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Medical University, Hefei 230022, China.
  • 2 Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
  • 3 Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
  • 4 Anhui Medical University, Hefei 230022, China.
  • 5 Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: [email protected].
  • 6 Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: [email protected].
  • 7 Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: [email protected].
PMID: 41577048 DOI: 10.1016/j.bcp.2026.117714
Abstract

Gastric Cancer (GC) is a major cause of morbidity and mortality worldwide; despite recent therapeutic advances, overall prognosis remains dismal due to late-stage diagnosis and therapeutic resistance. Among emerging mechanisms underlying tumor progression and therapeutic vulnerability, Ferroptosis is defined as an iron-dependent form of regulated cell death that is characterised by the process of lipid peroxidation, has been increasingly implicated in the initiation and progression of diverse malignancies, including gastric Cancer. In parallel, metabolic reprogramming has been recognized as a hallmark of Cancer, with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) gaining attention as a key bifunctional metabolic enzyme. By modulating intracellular levels of fructose-2,6-bisphosphate, PFKFB4 orchestrates the balance between glycolysis and the pentose phosphate pathway (PPP), thereby supporting redox homeostasis and anabolic growth. Notably, recent studies have identified aberrant overexpression of PFKFB4 in a range of malignancies, implicating it in tumor progression. Building on this, in the present study, we demonstrated that PFKFB4 is markedly overexpressed in GC cells and modulates their sensitivity to Ferroptosis through direct interaction with, and phosphorylation of, Heat Shock Protein Beta-1 (HSPB1), a critical negative regulator of ferroptotic signaling. Importantly, treatment with 5MPN, a specific inhibitor of PFKFB4, significantly potentiates ferroptotic cell death and suppresses GC tumor growth. These findings identify a previously unrecognized function of PFKFB4 in GC, extending beyond its canonical metabolic roles to include active regulation of Ferroptosis, thereby promoting Cancer progression. Consequently, pharmacological inhibition of PFKFB4 represents a promising therapeutic avenue for overcoming Ferroptosis resistance and suppressing tumor progression in gastric Cancer.

Keywords

Ferroptosis; Gastric cancer; HSPB1; PFKFB4.

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