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

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though mild in early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers, and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine. APPROACH AND RESULTS: Herein, we identified cyclin-dependent kinase-like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific Cdkl3 ablation developed severe MASLD-related hepatic inflammation, fibrosis, and diabetes. Mechanism-wise, CDKL3 directly phosphorylates forkhead box O (FoxO)1 on an unconventional site for the ubiquitination-dependent degradation of FoxO1, thereby remarkably alleviating glycogen and lipid accumulation and essentially preventing the onset of higher MASLD stages. Moreover, hepatic CDKL3 is a direct target gene of Hepatocyte nuclear factor 4α (HNF4α). HNF4α is inhibited during MASLD, which leads to diminished CDKL3 expression. The CDKL3-mediated cross talk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression. CONCLUSIONS: We unearthed an alternative but critical regulatory path of FoxO1 by the HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment.