J Hazard Mater. 2025 Jun 23;495:139049. doi: 10.1016/j.jhazmat.2025.139049. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic arsenic exposure is a global health concern linked to pulmonary diseases like fibrosis. However, its precise molecular mechanisms remain unclear. This study explored the effects of chronic arsenic exposure on a murine model (via diet) and BEAS-2B cells, focusing on oxidative stress, lipid peroxidation, mitochondrial dysfunction, and ferroptosis-mediated cell death.

METHODS: BEAS-2B cells were exposed to 1 μmol/L NaAsO₂ for 30 passages. Oxidative stress was assessed via ROS quantification, GSH depletion, and T-SOD activity. Lipid peroxidation was measured using BODIPY fluorescence and MDA levels. Mitochondrial dysfunction was determined by mtROS imaging and JC-1 staining. Ferroptosis was analyzed through GPX4 expression and TEM-based mitochondrial integrity. A 14-month murine model evaluated histopathology, metabolomic dysregulation, and gut-lung axis crosstalk.

RESULTS: Arsenic exposure significantly increased ROS, depleted GSH, and reduced T-SOD activity. Lipid peroxidation and mitochondrial dysfunction were evident, with more than 60 % decline in GPX4. Murine lung histology showed alveolar thickening, inflammatory infiltration, and elevated IL-6, TNF-α, and VEGF. Metabolomic analysis revealed disrupted lipid metabolism, correlating with ferroptosis markers (Acetyl-carnitine, L-Acetylcarnitine).

CONCLUSIONS: This was the first study to demonstrate ferroptosis as a key mechanism in arsenic-induced lung epithelial damage using a 14-month murine model and a 30-passage cellular model. We further demonstrated that ferroptosis induced by chronic exposure becomes functionally irreversible, as ferroptosis inhibition by Ferrostatin-1 failed to rescue GPX4 expression, unlike prior acute exposure models.

PMID:40614423 | DOI:10.1016/j.jhazmat.2025.139049

Ann Surg Oncol. 2025 Jul 3. doi: 10.1245/s10434-025-17738-3. Online ahead of print.

ABSTRACT

BACKGROUND: This study aimed to identify the most effective drug therapeutics for patients with the mesenchymal subtype of advanced gastric cancer (AGC). Extensive research employing diverse omics methodologies has unveiled a varied landscape of AGC. Recent progress in next-generation sequencing and other genomic technologies has facilitated a more intricate exploration of AGC at the molecular level. Nonetheless, the optimal treatment for patients with the mesenchymal subtype of gastric cancer remains elusive. Lei's molecular classification of AGC is based on gene expression profiles named "mesenchymal," "immunogenic," "classical," and "metabolic."

PATIENTS AND METHODS: Based on RNA-seq transcriptome, 234 patients were divided into four molecular subtypes: mesenchymal (n = 96), immunogenic (n = 37), metabolic (n = 61), and classic (n = 40).

RESULTS: Among those with mesenchymal-subtype AGC, compared with non-Apatinib group, the Apatinib treatment group demonstrated a significant increase in objective response rate (ORR 89.3% versus 69.3%, p = 0.038; odds ratio (OR) 0.269, 95% confidence interval (CI) (0.073-0.989)); overall survival (OS) 89.3% versus 60.2%, p = 0.010; hazard ratio (HR) 0.241, 95% CI (0.073-0.796)) and disease-free survival (DFS 78.6% versus 52.9%, p = 0.031; HR 0.400, 95% CI (0.167-0.956)). Furthermore, Apatinib significantly reduced the risk of death and recurrence in patients with mesenchymal subtype (OS: HR 0.129, 95% CI (0.030-0.563), p = 0.006; DFS: HR 0.340, 95% CI (0.138-0.833), p = 0.018). However, no significant differences were observed in the ORR, OS, or DFS between patients with metabolic and classical subtypes who underwent combination chemotherapy with additional Apatinib or camrelizumab.

CONCLUSIONS: Our analysis has revealed that, for neoadjuvant therapy in AGC, the mesenchymal subtype stands out as the ideal patient population benefiting from Apatinib.

PMID:40608168 | DOI:10.1245/s10434-025-17738-3