Targeting the ARF6-dependent recycling pathway to alter lipid rafts and reduce inflammation

Authors

Nigora Mukhamedova, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Andrew J. Fleetwood, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Kevin Huynh, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Yangsong Xu, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Tilly Van Buuren-Milne, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Alexandra Faulkner, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Ying Fu, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Farhad Parhami, MAX BioPharma Inc., Santa Monica, CA 90404, USA.
Peter J. Meikle, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, 3086, Australia.
Ilya Levental, Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22903, USA.
Michael Bukrinsky, Department of Microbiology, Immunology and Tropical Diseases, George Washington University, Washington, DC, 20037, USA.
Andrew J. Murphy, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Dmitri Sviridov, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3168, VIC, Australia. Electronic address: Dmitri.Sviridov@Baker.edu.au.

Document Type

Journal Article

Publication Date

9-16-2025

Journal

Journal of lipid research

DOI

10.1016/j.jlr.2025.100900

Keywords

ABCA1; Lipid raft; cholesterol; inflammation; membrane recycling; oxysterol; small GTPase

Abstract

Partitioning of inflammatory receptors into lipid rafts is essential for their function, making lipid rafts a promising target for anti-inflammatory therapies. However, the practical application of lipid raft-targeted therapies has been limited by a lack of mechanistic understanding of their regulation. In this study, we demonstrate that targeting the Arf6-dependent recycling pathway effectively modifies lipid rafts and mitigates inflammation. Using Oxy210, a synthetic oxysterol, we observed significant anti-inflammatory effects both in vivo and in vitro. These effects were linked to an increased abundance of ABCA1, enhanced cholesterol efflux, and alterations in the abundance and composition of lipid rafts. Mechanistically, Oxy210 disrupted the recycling checkpoint in late endosomes by reducing the abundance and activation of the small GTPase Arf6 and decreasing PI(4,5)P2 levels. This impaired lipid raft recycling to the cell surface and simultaneously reduced ABCA1 internalization. These findings highlight a novel approach to modulating lipid raft-dependent pathological pathways, with potential applications in treating inflammation, neurodegeneration, and infectious diseases.

APA Citation

Mukhamedova, Nigora; Fleetwood, Andrew J.; Huynh, Kevin; Xu, Yangsong; Van Buuren-Milne, Tilly; Faulkner, Alexandra; Fu, Ying; Parhami, Farhad; Meikle, Peter J.; Levental, Ilya; Bukrinsky, Michael; Murphy, Andrew J.; and Sviridov, Dmitri, "Targeting the ARF6-dependent recycling pathway to alter lipid rafts and reduce inflammation" (2025). GW Authored Works. Paper 7942.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7942

Department

Microbiology, Immunology, and Tropical Medicine