A translational systems medicine approach to devising nanotherapeutics for targeted intervention of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent substantial clinical burdens due to their multifactorial etiology and the paucity of available treatments. Despite the identification of numerous potential therapeutic targets and extensive clinical trials, so far, only a single drug has been approved for the treatment of MASH. This study proposes a conceptually new therapeutic design strategy grounded in an integrative, multidisciplinary approach. Utilizing bioinformatic analyses of clinical transcriptomic datasets, we identified ERN1 (IRE1α), a central component of the unfolded protein response, as a key regulatory node in MASLD progression. Leveraging this finding, we engineered a hepatoselective reactive oxygen species (ROS)-scavenging lipid nanoparticle (LNP) encapsulating KIRA6, a selective ERN1 kinase inhibitor. Preclinical evaluation in murine models of MASLD induced by the methionine-choline-deficient (MCD) diet or high-fat diet (HFD) revealed significant reductions in hepatic lipid accumulation and inflammation, along with marked attenuation of liver fibrosis. Our findings present a viable therapeutic candidate for MASLD/MASH and offer a conceptual framework for developing pathophysiology-informed treatment strategies against complex, multifactorial diseases.