KHSRP ameliorates acute liver failure by regulating pre-mRNA splicing through its interaction with SF3B1

Area of Science:

• Molecular Biology
• Hepatology
• Genetics

Background:

• Acute liver failure (ALF) presents a critical medical challenge with high mortality.
• Hepatic function rapidly deteriorates in ALF, necessitating effective interventions.
• Splicing factor dysregulation is implicated in ALF pathogenesis.

Purpose of the Study:

• To investigate the role of splicing factors in ALF.
• To identify potential therapeutic targets for ALF treatment.
• To elucidate the mechanism by which KHSRP influences ALF.

Main Methods:

• Proteomic and transcriptomic analyses in murine ALF models.
• KH-type splicing regulatory protein (KHSRP) knockdown experiments.
• Investigation of KHSRP interaction with splicing factor 3b subunit 1 (SF3B1).

Main Results:

• Multiple splicing factors, including KHSRP, were downregulated in ALF models.
• KHSRP knockdown led to splicing defects (e.g., intron retention) and worsened liver injury.
• KHSRP directly interacts with SF3B1, enhancing its binding to intronic branch sites and promoting pre-mRNA splicing.
• KHSRP demonstrated a protective effect against ALF in vivo by regulating pre-mRNA splicing.

Conclusions:

• KHSRP acts as a crucial splicing activator in the context of ALF.
• KHSRP interacts with SF3B1 to modulate gene expression relevant to ALF progression.
• KHSRP represents a promising therapeutic target for managing acute liver failure.