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

Ning Yao¹Xin Wang^1*Yajie Chen¹Yunjuan Wu¹Ying Su¹Xinxin Su¹Yajuan Geng¹Xiaoning Liu²Li-Min Tian^3*

• ¹Gansu University of Chinese Medicine, Lanzhou, China
• ²Lanzhou University, Lanzhou, China
• ³Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

Background: 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, mechanisms studies on Coptidis rhizoma remain limited. Purpose: To evaluate the therapeutic effects of Coptidis rhizoma on hepatic histological and functional damage, metabolic disorders, and insulin resistance in T2DM-related MASH, and to investigate its underlying mechanisms. Methods: Two-day-old male C57BL/6J mice were subcutaneously injected with streptozotocin (200 μg/20 μL per mouse). At 4 weeks of age, 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 4 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. Results: 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 with 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 hepatocytes of T2DM-related MASH mice, and both Coptidis rhizoma and epiberberine downregulated their expressions. Furthermore, Coptidis rhizoma and epiberberine suppressed the secretions of pro-inflammatory cytokines associated with the IL-17RA/ NF-κB pathway in hepatocytes. Conclusions: 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.