Language

English

Publication Date

4-29-2026

Journal

Antioxidants

DOI

10.3390/antiox15050566

PMID

42193188

PMCID

PMC13203856

PubMedCentral® Posted Date

4-29-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Air pollution is a growing hazard to global health. Epidemiological studies have reported a potential role of air pollutant exposure in the development or aggravation of neurodegenerative diseases. However, the underlying mechanisms are ill-defined. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of cell death that drives neuronal loss in neurodegenerative diseases. Our previous studies reported the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) and EPAC (exchange protein directly activated by cAMP) in ferroptotic cell death. Here, we investigated the effects of diesel exhaust particles (DEP) in mouse hippocampal (HT22) neuronal cells. Our data showed that toxicity induced by RSL3 (50-75 nM), a ferroptosis inducer, was significantly increased by the addition of DEP (100 μg/mL). Pharmacological inhibition of EPAC1 (CE3F4 30 μM or AM-001 30 μM) and soluble adenylyl cyclase (sAC; TDI-10229 1 μM or TDI-11861 0.1 μM) prevented enhanced ferroptotic HT22 cell death caused by DEP, while pharmacological modulation of EPAC2, protein kinase A (PKA), phosphodiesterases (PDEs), or transmembrane AC did not. DEP in combination with RSL3 exposure increased intracellular calcium levels and induced lysosomal de-acidification. Furthermore, inhibition of EPAC1 prevented mitochondrial ROS (MitoSOX) and lipid peroxidation (BODIPY C11 and MDA levels) after DEP and RSL3 co-exposure. Collectively, EPAC1 may serve as a novel target for the treatment or prevention of neurodegenerative diseases accelerated by air pollution.

Keywords

diesel exhaust particle, ferroptosis, EPAC, soluble AC, cAMP, oxidative stress

Published Open-Access

yes

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