2. Academic Validation
  3. Functional characterization of triokinase/FMN cyclase as a ferroptosis regulator and potential direct target of icaritin in hepatocellular carcinoma

Functional characterization of triokinase/FMN cyclase as a ferroptosis regulator and potential direct target of icaritin in hepatocellular carcinoma

  • Int J Biol Macromol. 2026 Apr:358:151597. doi: 10.1016/j.ijbiomac.2026.151597.
Wenpei Guo 1,  Haiyan Yue 2,  Chunan Zhou 1,  Jiefeng He 3,  Lixin Liu 4
Affiliations

Affiliations

  • 1 The First Clinical Medical College of Shanxi Medical University, Taiyuan, 030001, China; Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University, Taiyuan, 030000, China.
  • 2 State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
  • 3 Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China. Electronic address: [email protected].
  • 4 The First Clinical Medical College of Shanxi Medical University, Taiyuan, 030001, China; Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University, Taiyuan, 030000, China; Experimental Center of Science and Research, The First Hospital of Shanxi Medical University, Taiyuan, 030000, China; Key Laboratory of Prevention and Treatment of Liver Injury and Digestive System Neoplasms, Provincial Committee of the Medical and Health, Taiyuan, 030000, China. Electronic address: [email protected].
PMID: 41933761 DOI: 10.1016/j.ijbiomac.2026.151597
Abstract

Background: Triokinase/FMN cyclase (TKFC) is a bifunctional homodimeric enzyme in which the triokinase activity-requiring both the K and L domains from opposing subunits-catalyzes the ATP-dependent phosphorylation of triose sugars, while the L domain alone catalyzes the Mn2 + -dependent cleavage of FAD into cyclic FMN and AMP. Despite its metabolic importance, the role of TKFC in hepatocellular carcinoma (HCC) and regulated cell death remains unclear.

Methods: We employed clinical proteomics, multi-cohort validation, tissue microarray analysis, molecular dynamics simulations, cellular thermal shift assays (CETSA), and in vitro/in vivo models to investigate TKFC expression, prognostic significance, and ferroptosis-regulatory function.

Results: TKFC was significantly downregulated in HCC, with expression inversely correlating with tumor grade and positively with patient survival. TKFC overexpression inhibited proliferation, migration, and invasion while inducing Ferroptosis through elevated ROS, enhanced lipid peroxidation, and suppression of SLC7A11, GPX4, and FTH1. Molecular docking and 200 ns simulations revealed stable Icaritin (ICA) binding to TKFC, confirmed by CETSA in living cells. TKFC overexpression synergistically potentiated ICA-induced Ferroptosis and antitumor efficacy in vitro and in vivo.

Conclusion: This study establishes TKFC as an endogenous Ferroptosis regulator and direct molecular target of Icaritin in HCC, positioning it as both a prognostic biomarker and therapeutic target for precision therapy.

Keywords

Ferroptosis; Hepatocellular carcinoma; Icaritin; Molecular interaction; TKFC protein.

Figures
Products
Inhibitors & Agonists
Other Products