The Research Progress of Mechanism and the Role of Receptor-Interacting Protein Kinase 1 in Metabolic Dysfunction-Associated Steatohepatitis
CUI Xueying¹, ZHANG Jiaqiang¹, LIU Hanyun2*, GE Yuan1*
RIPK1 (receptor-interacting protein kinase 1) has emerged as a key nodal molecule in regulating cell death and inflammatory response. It plays critical roles in the progression of numerous human diseases such as psoriasis, neurodegenerative diseases, autoimmune disorders, and inflammatory liver diseases. MASH (metabolic dysfunction-associated steatohepatitis) is a metabolic inflammatory disease caused by multiple factors. Its prevalence has been increasing in recent years, posing a serious threat to human health. The function of RIPK1 in MASH exhibits a complex duality: it acts as an intrinsic protective factor in hepatocytes, inhibiting TNF-α-triggered apoptosis derived from liver macrophages, thereby maintaining liver homeostasis; on the other hand, under the chronic metabolic stress environment of MASH, RIPK1 kinase activity in liver macrophages may contribute to driving hepatocyte death and inflammation, exacerbating disease progression. This paradoxical nature makes RIPK1 an attractive therapeutic target, but also poses challenges for drug development: how to precisely inhibit the kinase activity of RIPK1 in liver macrophages. This article summarizes the latest research progress on RIPK1 and MASH treatment, and further explores whether inhibitors targeting the kinase activity of RIPK1 can specifically block the core pathological process of programmed cell death, reduce hepatocyte mortality, and thereby mitigate subsequent inflammatory responses and liver fibrosis. The aim is to provide new therapeutic strategies for halting the progression of MASH to more severe conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma.
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