Chiglitazar Demonstrates Potential to Treat Metabolic Dysfunction-Associated Steatohepatitis In Vitro and In Vivo.

INTRODUCTION

Chiglitazar was approved by the China National Medical Products Administration (NMPA) in 2021 for the treatment of patients with type 2 diabetes mellitus, and may also benefit from metabolic dysfunction-associated steatohepatitis (MASH).

METHODS

To characterise the role of Chiglitazar in MASH, in vitro experiments examining monocyte activation and migration were conducted, alongside liver and stellate cell proliferation assays. Three distinct MASH animal models (db/db mouse model, MCD model, CCl4 model) for conducting in vivo studies were established.

RESULTS

The results indicated that Chiglitazar reduced MCP-1-induced THP-1 migration and down-regulated TNF-α and MCP-1 expression. It also blocked TGF-β-driven proliferation in dermal fibroblasts and hepatic stellate cells while suppressing α-SMA and CTGF expression. In vivo, Chiglitazar alleviates hepatic steatosis and inflammation in the MCD model, whilst improving hepatic inflammation and fibrosis in both the CCL4 and HFD+CCL4 models.

DISCUSSION: In the study, it has been demonstrated that chiglitazar suppresses monocyte activation and chemotaxis, thereby attenuating chronic inflammation-elicited vascular and tissue damage. It also blocks fibroblast proliferation and differentiation, curbing toxin- or metabolite- induced inflammation and fibrosis. Although CCl4, MCD, and HFD+CCl4 models were used, they only partially reproduce human MASH pathology. Future work should employ more physiologically faithful systems.

CONCLUSION

As the world's first pan-PPAR agonist approved for the treatment of Type 2 Diabetes Mellitus (T2DM), Chiglitazar has also demonstrated potential for treating MASH by modulating steatosis, inflammation, and fibrosis. This potential may be translatable into clinical treatments in the foreseeable future.