# Coptidis rhizoma ameliorates type 2 diabetes mellitus-related metabolic dysfunction-associated steatohepatitis by downregulating the IL-17RA/NF-κB signaling pathway

## TL;DR

Coptidis rhizoma improves liver damage and metabolic issues in type 2 diabetes by reducing inflammation through a specific signaling pathway.

## Contribution

The study identifies the IL-17RA/NF-κB pathway as a target for Coptidis rhizoma in treating T2DM-related liver disease.

## Key findings

- Coptidis rhizoma reduced liver inflammation and improved liver function in T2DM-related MASH mice.
- The active compound epiberberine suppressed pro-inflammatory cytokines linked to the IL-17RA/NF-κB pathway.
- Downregulation of the IL-17RA/NF-κB pathway was observed in both in vivo and in vitro models.

## Abstract

Coptidis rhizoma, a botanical drug derived from the dried rhizome of Coptis species (e.g., Coptis chinensis), is characterized by abundant natural sources, significant bioactivity, and high safety. It holds considerable potential for translational applications in metabolic diseases, particularly in ameliorating type 2 diabetes mellitus (T2DM)-related metabolic dysfunction-associated steatohepatitis (MASH). However, mechanistic studies on Coptidis rhizoma remain limited.

This study aimed to evaluate the therapeutic effects of Coptidis rhizoma on hepatic histological and functional damage, metabolic disorders, and insulin resistance in T2DM-related MASH and investigate its underlying mechanisms.

Two-day-old male C57BL/6J mice were subcutaneously injected with streptozotocin (200 μg/20 μL per mouse). At 4 weeks of age, the mice were weaned and switched to a high-fat diet until week 9 to induce T2DM-related MASH. Starting from week 5, Coptidis rhizoma decoction was administered via oral gavage for four consecutive weeks to conduct in vivo studies. Additionally, hepatocytes were isolated from the model mice and exposed in vitro to epiberberine, the active metabolite of Coptidis rhizoma, for cellular-level investigations.

Coptidis rhizoma significantly attenuated hepatic inflammatory lesions, reduced the non-alcoholic fatty liver disease activity score, improved liver function, and alleviated glucose and lipid metabolism disorders and insulin resistance in a dose-dependent manner in T2DM-related MASH mice. At the transcriptional level, key components of the interleukin-17 receptor A (IL-17RA)/nuclear factor kappa B (NF-κB) signaling pathway were upregulated in the hepatocytes of T2DM-related MASH mice, and both Coptidis rhizoma and epiberberine downregulated their expressions. Furthermore, Coptidis rhizoma and epiberberine suppressed the secretion of pro-inflammatory cytokines associated with the IL-17RA/NF-κB pathway in hepatocytes.

Coptidis rhizoma ameliorates pathological phenotypes in T2DM-related MASH by inhibiting the IL-17RA/NF-κB signaling pathway, and its active metabolite epiberberine is involved in mediating these protective effects.