Novel Dual-Pharmacophore TrxR Inhibitors Integrating Ferroptosis and Antitumor Immunity: A Closed-Loop Strategy for...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Thioredoxin reductase (TrxR) overexpression correlates with poor liver cancer prognosis.
• Existing TrxR inhibitors lack dual pharmacophores and clear TIME regulation data.
• Dual-pharmacophore inhibitors offer novel therapeutic strategies.

Purpose of the Study:

• To develop novel dual-pharmacophore TrxR inhibitors using a traditional Chinese medicine-ligand synergistic strategy (TLSS).
• To investigate the antitumor activity and TIME-modulating effects of these inhibitors, particularly Fa-Au.
• To elucidate the underlying mechanisms of action, including ferroptosis and immunogenic cell death.

Main Methods:

• Synthesis and characterization of dual-pharmacophore TrxR inhibitors via TLSS.
• In vitro and in vivo evaluation of TrxR inhibition, tumor growth suppression, and TIME modulation.
• Mechanistic studies involving oxidative stress, ferroptosis, immunogenic cell death, and immune cell profiling.

Main Results:

• The compound Fa-Au demonstrated potent TrxR inhibition and significant tumor growth suppression.
• Fa-Au effectively remodeled the tumor immune microenvironment (TIME) by promoting M1 macrophage and dendritic cell maturation, enhancing CD8+ T cell activation, and reducing regulatory T cells (Tregs).
• Fa-Au induced oxidative stress and mitochondria-associated ferroptosis via TrxR/GPX4 downregulation, leading to immunogenic cell death (ICD) and activating an antitumor immune feedback loop.

Conclusions:

• Dual-pharmacophore TrxR inhibitors, exemplified by Fa-Au, represent a promising class of anticancer agents.
• Fa-Au exhibits potent antitumor activity by suppressing TrxR, inducing ferroptosis, and modulating the TIME.
• Fa-Au's mechanism involves an IFN-γ/STAT1/SLC7A11 axis, stimulating CD8+ T cells and inducing ferroptosis, highlighting its potential as a chemoimmunotherapeutic agent for liver cancer.