Journal Article Preprint Epublish
PubMed: 40502099 DOI: 10.1101/2025.06.02.657436
PDE10A Inhibition Disrupts Lipid Droplet Formation and Sensitizes Macrophages to Ferroptosis after LPS treatment.
bioRxiv
Authors: Bradford C Berk, Jinmin Zhang, Chia George Hsu
Affiliations
- Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Department of Physical Medicine and Rehabilitation, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
- Department of Kinesiology, The University of Texas at San Antonio, San Antonio, TX, USA.
- Department of Kinesiology, The University of Texas at San Antonio, San Antonio, TX, USA. Department of Molecular Microbiology and Immunology, The University of Texas at San Antonio, San Antonio, TX, US.
Abstract
Ferroptosis, an iron-dependent form of cell death, plays a key role in various diseases, but its impact on immune cells, particularly macrophages, remains unclear. This study explores how macrophage activation influences susceptibility to ferroptosis, focusing on lipopolysaccharide (LPS) and other inflammatory signals. We found that LPS priming enhanced resistance to ferroptosis in bone marrow-derived macrophages (BMDMs), as shown by reduced morphological changes, lower LDH release, and diminished cell death in real-time assays. Similar effects were observed with Zymosan A and TNF-α. Importantly, LPS-induced ferroptosis resistance was independent of stress response pathways like Nrf2 signaling. Instead, lipid droplet accumulation, driven by LPS, was central to this resistance. PDE10A inhibition reversed LPS-induced ferroptosis and reduced lipid droplet formation. LPS did not confer similar resistance in non-macrophage cell types, underscoring the macrophage-specific nature of this response. These findings highlight potential therapeutic targets for inflammatory diseases.
MeSH
Cells, Lipid Droplets, Macrophages, Ferroptosis, Therapeutics, Cell Death