Intracellular IL-24 ameliorates lipid metabolic disorders in metabolic dysfunction-associated steatohepatitis by restoring the autophagy-lysosome pathway
Jiawei Cui, Zhandong Lin, Mengjiao Sun, Yuyuan He, Yaoyao Mao, Congyue Zhang, Yue Shi, Yukai Chen, Shaoya Li, Ying Zhang, Qianqian Zheng, Yuemin Nan
TL;DR
This study shows that IL-24 helps treat liver disease by improving autophagy and reducing fat buildup in the liver.
Contribution
IL-24 is identified as a novel regulator of autophagy in MASH through the IL-22R1/IL-20R2 receptor complex.
Findings
IL-24 improves liver steatosis, inflammation, fibrosis, and insulin resistance in MASH mice.
IL-24 activates AMPK, suppresses mTOR, and enhances TFEB nuclear translocation to restore autophagy.
Multi-omics analysis links IL-24 to increased fatty acid oxidation and reduced glucose metabolism.
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is associated with impaired hepatic autophagy, but its key regulators remain unclear. This study delineates IL-24 as a regulator of autophagy in MASH. IL-24 was identified via bioinformatics in patient datasets and validated in metabolic dysfunction-associated steatotic liver disease (MASLD) patient sera. A high-fat high-fructose diet (HFFD) induced MASH in mice, with IL-24 overexpression via adeno-associated virus. Functional assessments were performed both in vivo and in primary hepatocytes using immunohistochemistry, Western blot, immunofluorescence, dual-fluorescence autophagic flux tracking, and multi-omics analyses. MASLD patients and animal models showed significantly lower IL-24 expression, with levels inversely related to disease severity. IL-24 intervention improved liver steatosis, inflammation, fibrosis, and insulin…
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Taxonomy
TopicsAutophagy in Disease and Therapy · Liver Disease Diagnosis and Treatment · Psoriasis: Treatment and Pathogenesis