Ruthenium(II) Lipid-Mimics Drive Lipid Phase Separation to Arouse Autophagy-Ferroptosis Cascade for...

Area of Science:

• Biochemistry
• Materials Science
• Immunology

Background:

• Lipid-mediated phase separation is vital for cellular processes like lipid metabolism and homeostasis.
• Dysregulation of lipid phase separation is linked to various cell death pathways.

Purpose of the Study:

• To develop novel ruthenium(II) lipid-mimics capable of inducing and monitoring lipid phase separation.
• To investigate the potential of these mimics in triggering immunogenic cell death and activating anti-tumor immunity.

Main Methods:

• Synthesis of Ru(II) lipid-mimics with varying lipid chain lengths.
• Characterization of Ru-LipM's ability to induce lipid phase separation via hydrocarbon chain-melting transitions.
• Assessment of Ru-LipM's impact on lipid metabolism, autophagy, ferritinophagy, and ferroptosis.
• Evaluation of Ru-LipM's in vivo anti-tumor efficacy and immune system activation.

Main Results:

• Ru-LipM, particularly with two dodecyl chains, effectively induces lipid phase separation.
• Ru-LipM treatment leads to increased polyunsaturated lipids, retarded autophagic flux, and enhanced ferritinophagy.
• Low-dose irradiation potentiates Ru-LipM-induced ferroptosis by deactivating GPX4 and upregulating ACSL4.
• Ru-LipM treatment invigorates both innate and adaptive immunity, demonstrating significant in vivo anti-tumor activity.

Conclusions:

• This study introduces Ru-LipM as a potent inducer of lipid phase separation and immunogenic cell death.
• Ru-LipM-mediated lipid phase separation and subsequent ferroptosis can be leveraged for anti-cancer immunotherapy.
• The developed Ru(II) lipid-mimics offer a promising biosimulation strategy for creating metal-based immune activators.