Halofuginone targets Serine/Glycine synthesis to reverse epidermal growth factor receptor Tyrosine Kinase inhibitor resistance in lung adenocarcinoma

  • Phytomedicine. 2025 Jul 25:143:156788. doi: 10.1016/j.phymed.2025.156788.
Yongping Li  1 ,  Peipei Liu  1 ,  Shiyao Liu  1 ,  Juan Zhu  1 ,  Yuehua Han  1 ,  Zuojie Jiang  1 ,  Dawei Tang  1 ,  Zixuan Meng  1 ,  Shanshan Li  2 ,  Mengxiao Zhang  2 ,  Yunlei Fan  1 ,  Fangtian Fan  2 ,  Pei Zhang  2 ,  Hao Liu  3
Affiliations
  • 1. School of Pharmacy, Bengbu Medical University, Bengbu, 233000, China.
  • 2. School of Pharmacy, Bengbu Medical University, Bengbu, 233000, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu Medical University, Bengbu, 233000, China.
  • 3. School of Pharmacy, Bengbu Medical University, Bengbu, 233000, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu Medical University, Bengbu, 233000, China. Electronic address: [email protected].
PMID: 40354707 DOI: 10.1016/j.phymed.2025.156788
Abstract

Background: An emerging issue is that patients are prone to become resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) which are the first- line treatment for EGFR-mutated non-small cell lung Cancer (NSCLC) after approximately 10 months of drug administration. Interestingly, metabolic dysregulation occurs simultaneously with acquired EGFR-TKI resistance in certain NSCLC cell lines.

Purpose: We aimed to investigate whether a natural product, halofuginone (HF), could overcome NSCLC resistance to EGFR-TKIs by influencing metabolism.

Results: In our study, the combination of HF and EGFR-TKI exhibited synergistic cytotoxicity compared to EGFR-TKI monotherapy. The underlying mechanism is that HF promotes the degradation of SP1 protein and decreases the expression of phosphatidylserine transcarbamoylase 1 (PSAT1), which leads to defects in the de novo synthesis of Serine/Glycine and cell death.

Conclusions: HF is a promising natural product for overcoming NSCLC resistance to third-generation epidermal growth factor receptors-TKIs.

Keywords
EGFR-TKI; Halofuginone; NSCLC; Resistance; Serine/Glycine.
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