EGF/STAT1 signals to maintain ECM1 expression in hepatic homeostasis are disrupted by IFNγ/NRF2 in chronic liver disease

Li, Y.; Link, F.; Fan, W.; Nwosu, Z. C.; Pioronska, W.; Gould, K.; Meyer, C.; Yao, Y.; Hammad, S.; Feng, R.; Liu, H.; Shao, C.; Sun, B.; Ding, H.; Liebe, R.; Ebert, M. P. A.; Weng, H.-L.; ten Dijke, P.; Dooley, S.; Wang, S.

doi:10.1101/2024.02.17.580798

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bioRxiv · 10.1101/2024.02.17.580798

EGF/STAT1 signals to maintain ECM1 expression in hepatic homeostasis are disrupted by IFNγ/NRF2 in chronic liver disease

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Abstract

In healthy livers, extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-{beta} (LTGF-{beta}) quiescent. Upon hepatocyte damage, ECM1 is downregulated, facilitating LTGF-{beta} activation and fibrogenesis. However, little is known about how hepatic ECM1 is regulated. Here we found in healthy hepatocytes, EGF/EGFR signaling sustains ECM1 expression through phosphorylating STAT1 at S727, enhancing its binding to the ECM1 promoter and boosting gene transcription. During liver inflammation, accumulating IFN{gamma} disrupts this process by downregulating EGFR and inhibiting EGF/EGFR/STAT1-mediated ECM1 promoter binding. Mechanistically, IFN{gamma}-induced STAT1 phosphorylation at Y701 impairs the binding of p-STAT1 S727 to the ECM1 promoter. Additionally, IFN{gamma} induces NRF2 nuclear translocation, which repressively binds to the ECM1 promoter, further reducing its expression. These findings were confirmed in several chronic liver disease (CLD) mouse models. Moreover, AAV8-ECM1 significantly attenuates liver fibrosis and injuries in Western diet (WD)-fed mice. Notably, in patients with CLD, ECM1 levels align with EGFR expression, while NRF2 and LTGF-{beta} activation show a negative correlation with both.

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Li, Y., Link, F., Fan, W., Nwosu, Z. C., Pioronska, W., Gould, K., Meyer, C., Yao, Y., Hammad, S., Feng, R., Liu, H., Shao, C., Sun, B., Ding, H., Liebe, R., Ebert, M. P. A., Weng, H.-L., ten Dijke, P., Dooley, S., Wang, S.. 2024-02-19. EGF/STAT1 signals to maintain ECM1 expression in hepatic homeostasis are disrupted by IFNγ/NRF2 in chronic liver disease. https://doi.org/10.1101/2024.02.17.580798

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