Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis.

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Ap alladium-catalyzed cross-coupling reaction with aryl halidef unctionalities has recently emerged as avaluable tool for protein modification. Herein, an ew fluorogenic modificationm ethodology for proteins,w ith genetically encoded fluorosulfate-l-tyrosine, which exhibits high efficiency and biocompatibility in bacterial cells as wella si n aqueous medium, is described. Furthermore, the cross-coupling of 4-cyanophenylboronic acid on green fluorescent protein was shown to possessaunique fluorogenic property, whichc ould open up the possibility of ar esponsive "off/on" switchw ith great potential to enables pectroscopici maging of proteins with minimal backgroundnoise.T aken together, ac onvenient ande fficient catalytic system has been developed that mayp rovide broadu tilities in protein visualization and live-cell imaging.

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A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22414-7