Intranasal Exposure of NCM811 Induces Pulmonary Injury by Driving Phenotypic Alveolar Macrophages Reprogramming via Lysosome-Peroxisome Crosstalk

Abstract

Increasing environmental dissemination of LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode raises inhalation exposure concerns. However, the systemic toxicological profile and mechanisms of action of it remain poorly understood. This study investigated NCM811-induced toxicity to identify primary target organs and elucidated the underlying mechanisms. We demonstrated that exposure of NCM811 induce multiorgan impairment, with the lung as the primary target, evidenced by the highest histopathological scores (6.75 ± 0.875) and maximal tissue accumulation of NCM-derived metals. Pulmonary injury was characterized by respiratory dysfunction (a 1.36-fold increase in lung volumes and gas trapping) and extensive alveolar destruction (>50% architectural collapse). NCM811 exposure orchestrated pathogenic reprogramming of alveolar macrophages from pro-repair to pro-injury phenotype via a novel lysosome-peroxisome crosstalk, ultimately leading to 44% decrease in epithelial regeneration. In depth, this crosstalk was initiated by the release of lysosomal proteases, particularly cathepsin B, following particle phagocytosis. Pharmacological inhibition of cathepsin B effectively reversed this shift, confirming its pivotal role in driving phenotypic programming. Our findings prioritize the lungs for surveillance in NCM811 exposure, identifying the injurious phenotypic shift of alveolar macrophages as a cellular biomarker for early detection and the protease-driven lysosome-peroxisome crosstalk as a key therapeutic target.