Confined Oxidative Catabolism: Organelle-Level Reactive Oxygen Species for Precision Intervention in Metabolic-Associated Fatty Liver Disease.

Abstract

Lipid droplets are central organelles for energy storage, yet their abnormal expansion is a key driver of metabolic-associated fatty liver disease (MAFLD). Targeting lipid metabolism has emerged as a promising therapeutic strategy; however, existing approaches largely focus on systemic metabolic regulation and lack the ability to precisely manipulate lipid breakdown within lipid droplets. Here, we developed a molecularly engineered lipid droplet-targeting compound, BrBD, through a modular synthesis involving acid-catalyzed construction of a BODIPY scaffold followed by bromination that enables confined and spatiotemporally controllable modulation of intradroplet lipid catabolism. BrBD selectively accumulates in lipid droplets and generates reactive oxygen species (ROS) on demand via photoactivation. The locally produced ROS promotes lipid peroxidation and subsequently activates dual catabolic pathways, lipolysis and lipophagy, leading to efficient lipid droplet clearance. In a MAFLD mouse model, this subcellularly confined ROS strategy significantly alleviated hepatic steatosis with minimal off-target effects, owing to the on-demand and spatially restricted nature of ROS generation. Our work establishes a "confined oxidative catabolism" strategy for precise organelle-level metabolic intervention, offering a therapeutic avenue for lipid-related disorders.