Targeting ROAM1 with UDP-GlcNAc nanosheets selective activates lysosomal AMPK to resolve metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease with limited treatment options. Although AMP-activated protein kinase (AMPK) has been implicated in multiple pathological processes and represents a highly promising therapeutic target for MASLD, the clinical efficacy of AMPK activators has been unsatisfactory, possibly due to overly abundant substrate and the complex activation mechanisms of AMPK. Recent work on lysosome-specific activation of AMPK has revealed a preference for metabolic substrate activation, highlighting it as a potential target for precision therapy of MASLD. Here, through a bimolecular fluorescence complementation (BiFC)-based protein interaction screen, we identify the nucleotide-sugar transporter ROAM1 (renamed from SLC35F6) as an AMPKβ-interacting protein that localizes to the lysosome and negatively regulates AMPK activity. Silencing ROAM1 in mouse liver and muscle elevates basal AMPK activity and induces a transcriptional state that inhibits lipid synthesis. UDP-GlcNAc is the ligand of ROAM1 and activates lysosomal AMPK through the ROAM1-AMPKbeta axis to primarily regulate lipid metabolism. To evaluate the therapeutic effect of this pathway on MASLD, we engineered a magnesium-coordinated UDP-GlcNAc nanosheet (MgUGN) for efficient in vivo delivery. MgUGN treatment improves lipid metabolism and reduces hepatic steatosis in metabolic disease models, and mitigates liver damage in acute injury models by decreasing inflammation. These findings identify the UDP-GlcNAc-ROAM1-AMPK axis as a regulator of hepatic lipid metabolism and introduce MgUGN as a novel compartment-specific AMPK activator for liver disease.