Epidemiological studies have linked fine dust pollution to depression, yet the underlying mechanisms remain unclear. Oxidative stress and endoplasmic reticulum (ER) stress are known contributors to depression, but their induction by particulate matter (PM), particularly PM2.5, in animal models has been limited. This study aimed to establish a rat model of PM2.5-induced depression-like behaviors and elucidate the underlying molecular mechanisms. Adult male Sprague–Dawley rats received daily intranasal PM2.5 for four weeks. Behavioral assessments, including the open field test (OFT), forced swim test (FST), and light-dark box (LDB) test, were conducted weekly. PM2.5-exposed rats displayed depressive-like behaviors, particularly in the FST, reflecting decreased motivation and learned helplessness. Molecular analyses indicated a specific increase in ER stress markers (CHOP, eIF2α, GRP78, and P16) and NOX4 in the hypothalamus, while other brain regions (striatum, cortex, and hippocampus) were not as pronounced. Additionally, PM2.5 exposure reduced tyrosine hydroxylase (TH) levels in the hypothalamus, suggesting impaired dopamine synthesis. These findings indicate that PM2.5 induces depressive-like behaviors via hypothalamic ER stress and oxidative stress pathways, leading to dopaminergic dysfunction. Targeting oxidative and ER stress within the hypothalamus may offer new therapeutic strategies for treating depression associated with environmental pollutants.

Saturated fatty acids impose lipotoxic stress on pancreatic β cells, leading to β cell failure and diabetes. In this study, we investigate the critical role of organellar Ca ²⁺ disturbance on defective autophagy and β cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca ²⁺ elevation, sustained mTOR complex 1 (mTORC1) activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in β cells. These Ca ²⁺ aberrations with autophagy defects by palmitate were prevented by an mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca ²⁺ overload, strategies such as lowering extracellular Ca ²⁺ , employing voltage-gated Ca ²⁺ channel blocker or ATP-sensitive K ⁺ channel opener, effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca ²⁺ into the endoplasmic reticulum (ER), with an ER Ca ²⁺ ATPase activator, restored TRPML1 activity, promoted autophagic flux, and improved survival of β cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress/Ca ²⁺ overload/mTORC1 pathway involvement in TRPML1 suppression and defective autophagy during β cell lipotoxicity. Restoring perilysosomal Ca ²⁺ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.