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bioRxiv · 10.1101/2025.04.09.648024

Targeting CRM1-HMGB1 Nuclear Translocation in Type 2 Diabetes-Driven Metabolic Dysfunction Associated Steatotic Liver Disease

Paramasivam, P.·Bravo, G. M.·Coffman, B. B.·Rajaiya, J.·Monga, S. P.·Alvidrez, R. I. M.
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Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) prevalent in Type-2 Diabetes (T2D) and contributes to progression of Non-Alcoholic Steatohepatitis (NASH). Acetyl-High Mobility Group Box 1 (HMGB1,) a proinflammatory isoform of HMGB1, is released as a DAMP in T2D associated hepatic inflammatory condition. Chromosomal Maintenance 1 (CRM1), a nuclear transporter protein, maintains the nuclear-cytoplasm translocation of hepatic HMGB1 in T2D. We hypothesize that inhibition of CRM1/HMGB1 nuclear shuttling is a therapeutic target for MASLD in T2D. Methods: We performed immunohistochemical analysis of acetyl-HMGB1 and CRM1 in human liver biopsies from control, T2D, and T2D-NASH (n:4 per group). H&E staining to evaluate inflammation and disease stratification. In vitro, studies involved targeted inhibition of CRM1 using Leptomycin-B and HMGB1 with Glycyrrhizin in T2D Huh7 human hepatocytes. Results: T2D subjects with NASH exhibit an increase in acetyl-HMGB1 nuclear and cytoplasmic translocation compared to DM and controls. Acetyl-HMGB1 increased 2-fold in the nucleus and 4-fold in the cytoplasm; CRM1 increased 6-fold in the nucleus and 8-fold in the cytoplasm of T2D/NASH subjects compared to controls. Targeted inhibition of CRM1 and HMGB1 prevented acetyl-HMGB1 hepatocyte release with the most prominent effect in T2D-NASH conditions. Conclusions: Hepatic CRM1/HMGB1 inhibition could be a potential therapeutic target for T2D-driven MASLD.

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Paramasivam, P., Bravo, G. M., Coffman, B. B., Rajaiya, J., Monga, S. P., Alvidrez, R. I. M.. 2025-04-15. Targeting CRM1-HMGB1 Nuclear Translocation in Type 2 Diabetes-Driven Metabolic Dysfunction Associated Steatotic Liver Disease. https://doi.org/10.1101/2025.04.09.648024

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