PM_2.5 induces autophagy‐dependent ferroptosis by endoplasmic reticulum stress in SH‐SY5Y cells

Abstract

Fine particulate matter (PM2.5) has been a global environmental problem threatening public health in recent years. PM2.5 exposure was associated with an increased risk of neurodegenerative diseases related to neuronal apoptosis. Ferroptosis is a nonapoptotic form of programmed the cell death, characterized by excess iron‐dependent lipid peroxidation products. Whether PM2.5 could induce ferroptosis in cells and thus be involved in its neurotoxicity is unknown. In this study, we found that PM2.5 induced endoplasmic reticulum stress, apoptosis, autophagy, and ferroptosis in neuroblastoma human neuroblastoma cells (SH‐SY5Y). Interestingly, ferroptosis was the predominant form of mortality in the presence of high doses of PM2.5 exposure. In addition, the endoplasmic reticulum stress inhibitor 4‐phenylbutyric acid (4‐PBA) inhibited PM2.5‐induced cellular autophagy, apoptosis, and ferroptosis. Autophagy inhibitors chloroquine (CQ) alleviated PM2.5‐induced ferroptosis but did not reverse apoptosis. We also found that inhibition of both endoplasmic reticulum stress and autophagy reversed the PM2.5‐induced increase in the expression level of cytophagy nuclear receptor coactivator 4 (NCOA4). Our results suggested that PM2.5‐induced ferroptosis in SH‐SY5Y cells was autophagy‐dependent ferroptosis due to endoplasmic reticulum stress, which might be associated with the elevation of iron content caused by NCOA4‐mediated ferritin autophagy.

Particulate Matter-Induced Neurotoxicity: Unveiling the Role of NOX4-Mediated ROS Production and Mitochondrial Dysfunction in Neuronal Apoptosis

“…PM-induced neurotoxicity encompasses mechanisms beyond the NOX4-mediated apoptosis pathway, including endoplasmic reticulum stress, ERK/CREB pathway inhibition, ferroptosis induction [ 8 , 39 ], and inflammatory cytokine secretion [ 31 ]. PM-mediated ROS generation involves multiple pathways, such as the inflammatory response, hydroxyl radical formation, and NOX activation.…”

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis

“…L-citrulline, an endogenous metabolite in the urea cycle, restrains ferroptosis-induced thymus damage and preserves immune function in mice [ 269 ]. The cytotoxic effects induced by various agents such as nanoparticles [ 270 , 271 ], arsenic [ 272 , 273 ], antimony [ 121 ], PM2.5 [ 274 , 275 ], cadmium telluride [ 276 ], and ionizing radiation [ 277 ] can also be inhibited through genetic or pharmacological inhibition of ADF. These findings suggest that suppressing ADF might mitigate the toxic effects of these agents.…”

Spotlight on iron and ferroptosis: research progress in diabetic retinopathy

“…Recent findings by Wang et al (80) have demonstrated that HG can elevate ER stress by upregulating MALAT1 expression, thereby increasing the levels of TNF-a and IL-6. Simultaneously, ER stress can trigger NCOA4mediated ferritin autophagy, culminating in iron overload, while concomitantly suppressing PPARg expression, thereby enhancing the susceptibility to ferroptosis (77,81). Furthermore, ER stress contributes to the activation of the BMP/SMAD signaling pathway by inhibiting TMPRSS6 and stabilizing hepcidin mRNA through the RNA-binding protein HuR.…”