Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though being mild at 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 FoxO1 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 HNF4α. HNF4α is inhibited during MASLD, which led to diminished CDKL3 expression. The CDKL3-mediated crosstalk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression. Conclusions: We unearthed an alternative but critical regulatory path of FoxO1 by HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment.

中文翻译：

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HNF4α-CDKL3 轴通过非经典磷酸化靶向 FoxO1 来限制 MASLD 进展


背景和目的： 代谢功能障碍相关脂肪性肝病 （MASLD） 是一种具有广泛症状的全球性疾病。虽然早期 MASLD 较轻，但 MASLD 的进一步发展会导致脂肪性肝炎、肝硬化、肝癌和伴随的糖尿病。发现 MASLD 进展中的关键调节因子在基础医学和转化医学中都具有重要价值。方法和结果： 在此，我们确定了细胞周期蛋白依赖性激酶样 3 （CDKL3） 是 MASLD 进展的主要守护者。肝脏特异性 Cdkl3 消融的小鼠发展为严重的 MASLD 相关肝脏炎症、纤维化和糖尿病。在机制方面，CDKL3 在非常规位点直接磷酸化 FoxO1，以实现 FoxO1 的泛素化依赖性降解，从而显著减轻糖原和脂质的积累，并从根本上阻止更高 MASLD 阶段的发生。此外，肝脏 CDKL3 是 HNF4α 的直接靶基因。HNF4α 在 MASLD 期间受到抑制，导致 CDKL3 表达减少。因此，CDKL3 介导的 HNF4α 和 FoxO1 串扰在 MASLD 进展中形成反馈回路。结论： 我们通过 HNF4α-CDKL3 轴发现了 FoxO1 的另一种但关键的调控途径。CDKL3 可作为 MASLD 的守护者，也可作为 MASLD 治疗中 FoxO1 抑制剂的预后指标。