Abstract
Obesity and related metabolic disorders, including metabolic dysfunction-associated steatohepatitis (MASLD), have reached epidemic proportions worldwide. We unveil a previously unknown moonlighting role for arginase 1 (Arg1) in facilitating hepatic lipogenesis. Male mice lacking hepatic Arg1 exhibit diminished lipid accumulation in both liver and adipocytes, an effect mirrored in genetically- or diet-induced obesity models following Arg1 inhibitor treatment. Mechanistically, Arg1 competes with RSK2 and Elk1 for binding to the substrate-binding pocket of extracellular signal-regulated kinase 2 (ERK2) via its S-shaped motif, thereby enhancing ERK2 ubiquitination and degradation and upregulating the AKT/mTOR/PPARγ and Elk1/c-Fos/PPARγ cascades, ultimately augmenting lipogenesis. Peptides designed to mimic the ERK2 substrate-binding pocket disrupt the Arg1-ERK2 interaction and improve metabolic profiles in obesity and MASLD models. Our findings implicate Arg1 regulates hepatic lipid metabolism via its physical interaction with ERK2, highlighting the Arg1-ERK2 interaction as a promising therapeutic target for obesity and related metabolic disorders in male mice.
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Data availability
mRNA-seq data generated in this study have been deposited at the National Center for Biotechnology Information (NCBI) GenBank (PRJNA1186374 [https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1186374] and PRJNA1186081. Microscopy data reported in this paper will be shared by the lead contact upon request. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD059821. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Source data are provided in this paper.
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Acknowledgements
This research was supported by the Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 82200649), the National Natural Science Foundation of China (Grant No. 82472241). We would also like to acknowledge the help of HUABIO and WZ Biosciences Inc. in providing peptides as well as virus strains. We are grateful to Shanghai Oe Biotech Co., Ltd., for providing sequencing services.
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M.S. and X.C. conceived and designed the project. Y.C. performed mRNA-seq experiments and analysis. M.S., Z.Z., Y.S., Q.T., Q.X., T.M., Z.W., M.C., Y.Z., and R.Y. bred mice, performed mouse experiments, and analyzed the data. M.S., J.G., and J.Y. provided liver disease model setup, study design, and joint discussions on the results. Y.S. and M.S. interpreted the data and drafted and revised the manuscript.
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Shao, M., Cao, X., Chen, Y. et al. Arginase 1 promotes hepatic lipogenesis by regulating ERK2/PPARγ signaling in a non-canonical manner. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69731-3
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DOI: https://doi.org/10.1038/s41467-026-69731-3
