Cobalt Hexacyanoferrate Nanocatalysts Combat Acute Lung Injury via Ferroptosis-Based Regulation of Iron Homeostasis and Antioxidant Defenses

Acute lung injury (ALI) represents a life-threatening condition with limited therapeutic options. Emerging evidence suggests that ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, is a key pathological mechanism underlying ALI. Therefore, we systematically investigated the key role of ferroptosis in ALI pathogenesis using a lipopolysaccharide (LPS)-induced mouse model of sepsis-related ALI. Based on this finding, we engineered polyvinylpyrrolidone-assembled cobalt hexacyanoferrate nanocatalysts (CoHCF NCs) as a ferroptosis inhibitor. These nanocatalysts exhibited dual functions: efficient chelation of free iron ions and strong antioxidant activity. In vivo experiments showed the promising therapeutic efficacy of CoHCF NCs, while in vitro studies using erastin-induced ferroptosis in alveolar epithelial cells confirmed their strong ability to reverse ferroptotic processes. To explore the underlying mechanisms, we employed RNA sequencing, which revealed that CoHCF NCs exert their antiferroptotic effects through a transcriptional network involving antioxidant response enhancement, and iron ion homeostasis regulation. Due to their high ferroptosis-inhibitory capacity and biocompatibility, CoHCF NCs represent a promising therapeutic candidate for ALI.