HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via noncanonical phosphorylation

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Diseases

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with progressive stages including steatohepatitis, cirrhosis, and liver cancer.
• MASLD often co-occurs with diabetes, highlighting the systemic metabolic impact.
• Identifying key regulators of MASLD progression is crucial for therapeutic advancements.

Purpose of the Study:

• To identify critical regulators involved in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD).
• To elucidate the molecular mechanisms by which these regulators impact MASLD pathogenesis.
• To explore potential therapeutic targets for MASLD treatment.

Main Methods:

• Utilized a mouse model with liver-specific ablation of cyclin-dependent kinase-like 3 (CDKL3).
• Investigated the phosphorylation and degradation pathways of forkhead box O (FoxO)1.
• Analyzed the regulatory relationship between Hepatocyte nuclear factor 4α (HNF4α) and CDKL3 in MASLD.

Main Results:

• CDKL3 acts as a key protector against MASLD progression, with its deficiency leading to severe hepatic inflammation, fibrosis, and diabetes.
• CDKL3 directly phosphorylates FoxO1, promoting its degradation and reducing hepatic lipid and glycogen accumulation.
• MASLD inhibits HNF4α, which in turn reduces CDKL3 expression, establishing a feedback loop involving HNF4α and FoxO1.

Conclusions:

• Discovered a novel regulatory pathway involving the HNF4α-CDKL3 axis that controls FoxO1 stability.
• CDKL3 functions as a critical guardian against MASLD progression.
• CDKL3 may serve as a prognostic marker for MASLD patients, particularly those treated with FoxO1 inhibitors.