Itaconic acid ameliorates necrotizing enterocolitis through the TFEB-mediated autophagy-lysosomal pathway

Abstract

Excessive autophagy has been implicated in the pathogenesis of necrotizing enterocolitis (NEC), yet the molecular underpinnings of the autophagy-lysosomal pathway (ALP) in NEC are not well characterized. This study aimed to elucidate alterations within the ALP in NEC by employing RNA sequencing on intestinal tissues obtained from affected infants. Concurrently, we established animal and cellular models of NEC to assess the therapeutic efficacy of itaconic acid (ITA). Our results indicate that the ALP is significantly disrupted in NEC. Notably, ITA was found to modulate the ALP, enhancing autophagic flux and lysosomal function, which consequently alleviated NEC symptoms. Further analysis revealed that ITA's beneficial effects are mediated through the promotion of TFEB nuclear translocation, thereby augmenting the ALP. These findings suggest that targeting the ALP with ITA to modulate TFEB activity may represent a viable therapeutic approach for NEC.

Keywords: Autophagy-lysosomal pathway; Itaconic acid; Lysosomal dysfunction; Necrotizing enterocolitis; TFEB.