The role of NEDD4L in metabolic dysfunction-associated fatty liver disease (MAFLD) by regulating ferroptosis via deubiquitinating the TGF-β receptor TβRII.

We explored the mechanism of E3 ubiquitin ligase neural precursor cell expressed developmentally down regulated 4-like protein (NEDD4L) mediating ferroptosis sensitivity through the transforming growth factor-beta1 (TGF-β1) signaling to regulate high-fat and high-sugar diet (HFHS)-induced liver injury in HFHS feeding-induced metabolic dysfunction-associated fatty liver disease (MAFLD) mice. NEDD4L was poorly expressed in liver tissues of HFHS-induced MAFLD mice. NEDD4L overexpression ameliorated HFHS-induced liver injury in MAFLD mice. Mechanistically, NEDD4L overexpression repressed ferroptosis sensitivity in liver tissues and ameliorated HFHS-induced liver injury in MAFLD mice. NEDD4L hindered the TGF-β1 signaling by mediating TβRII ubiquitin degradation. Activation of the TGF-β1 signaling partially abrogated NEDD4L overexpression-ameliorated ferroptosis in liver tissues and HFHS-induced liver injury of MAFLD mice. NEDD4L might hinder the TGF-β1 signaling and inhibit ferroptosis sensitivity by mediating TβRII ubiquitin degradation, thereby improving HFHS-induced liver injury in MAFLD mice.