Targeted inhibition of MLKL-mediated necroptosis attenuates chronic arsenite exposure-induced lung injury

作者：Yinan Liu, Yonghui Chen, Meng Zhang, Yawen Shi, Yixin Cui, Xinhe Zhang, Lian Li, Xu Zhao, Pinglin Yang, Jinghong Chen · 发表于：Ecotoxicology and Environmental Safety · 年份：2025 · DOI：10.1016/j.ecoenv.2025.119216 · 被引用次数：1 · 研究领域：Cell death mechanisms and regulation、Trace Elements in Health、Heavy Metal Exposure and Toxicity

Arsenic, a ubiquitous environmental toxicant, poses a global public health concern through drinking water contamination. While chronic arsenic exposure is epidemiologically associated with respiratory diseases, the molecular mechanisms driving its pulmonary toxicity remain incompletely understood. Emerging evidence implicates necroptosis—a regulated cell death pathway mediated by the RIPK1-RIPK3-MLKL axis—is implicated in diverse diseases, though its contribution to arsenic-induced pulmonary injury is uncharacterized. This study aims to elucidate the contribution of necroptosis to arsenic-induced lung injury using both in vitro and in vivo models. We treated human lung epithelial cells (BEAS-2B) with sodium arsenite (NaAsO 2 ) and applied specific necroptosis inhibitors. Cell viability, apoptosis, and phosphorylation of RIPK3 (p-RIPK3) and MLKL (p-MLKL) were assessed via CCK-8 assay, flow cytometry, and Western blot, respectively. Additionally, chronic arsenic exposure models were generated in wild-type (WT) and MLKL knockout ( Mlkl -/- ) mice. Lung histopathology, fibrosis, inflammatory markers (IL-6, CC16 and TNF-α), and necroptosis markers (p-RIPK3, and p-MLKL) were analyzed using H&E staining, Masson staining, ELISA, immunohistochemistry, and Western blot. Results showed that NaAsO 2 induced dose-dependent cytotoxicity and RIPK3/MLKL phosphorylation in BEAS-2B cells, effects that were reversed by necroptosis inhibition. In mice, arsenic exposure promoted interstitial thic...