NPRC promotes hepatic steatosis via USP30-mediated deubiquitination of C/EBPβ

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition characterised by dysregulated lipid metabolism. The role of Natriuretic Peptide Receptor C (NPRC), a receptor responsible for clearing natriuretic peptides, in MAFLD remains elusive. Therefore, the aim of the present study was to elucidate the role of NPRC in MAFLD progression. Approach and results: This study demonstrated that NPRC enhanced lipid metabolism reprogramming and accelerated MAFLD progression. Mechanistic investigations, including proteomic and ubiquitination analyses, revealed that elevated NPRC levels stabilized the C/EBP(3 protein, leading to excessive lipid accumulation. The DNA-binding domain (DBD) of C/EBP(3 interacted with the deubiquitinase USP30, a key regulator that inhibited K149-specific K48-linked polyubiquitination of C/EBP(3. Importantly, the ANPR region of NPRC bound to USP30, facilitating the deubiquitination of C/EBP(3. Furthermore, virtual screening identified punicalin, a natural compound, as a potential inhibitor of NPRC expression, which may reduce hepatic lipid accumulation, inflammation and fibrosis. Conclusions: Our findings indicate that NPRC recruits USP30 to mediate the deubiquitination of C/EBP(3, driving lipid metabolism reprogramming. Targeting NPRC could represent a promising therapeutic approach for MAFLD.