Non-alcoholic fatty liver disease (NAFLD) is well recognized as the primary etiology of chronic hepatic disorders, with a prevalence of roughly 25 % among the adult population worldwide [1,2]. NAFLD comprises a range of diseases that span from the presence of simple liver steatosis and fibrosis to the development of cirrhosis [3]. Liver transplantation is presently the sole viable therapeutic intervention for end-stage cirrhosis; nevertheless, the insufficiency of accessible organs is a substantial constraint [4]. The treatment options most commonly indicated for NAFLD encompass the use of antioxidants, lipid-lowering medications, and lifestyle adjustments. Nevertheless, the current medical landscape lacks definitive and certain therapeutic interventions for NAFLD. Hence, it is imperative to augment the current understanding of the processes that underlie hepatic steatosis and investigate novel approaches for therapy.

The mitochondrion, a cellular organelle that governs cellular redox, lipid metabolism, and cell death processes, assumes a crucial role in hepatic function. Mitophagy, a process that selectively targets damaged or redundant mitochondria for elimination through autophagy, is crucial for maintaining mitochondrial homeostasis [5]. Recent findings indicate that there is a significant impairment of mitophagy in NAFLD, and this deficiency in mitophagy is closely linked to the progression of hepatic injury [6,7]. Hepatic mitophagy has a beneficial role in regulating both acute and chronic hepatic damage. The process of BNIP3-mediated mitophagy aids in the preservation of mitochondrial function and enhances the survival of hepatocytes in cases of fatty liver disease by eliminating depolarized mitochondria and lipid molecules [8]. The targeting of PTEN-induced kinase 1 (PINK1)-mediated mitophagy represents a significant therapeutic approach for the management of NAFLD in murine models [9]. However, the precise regulatory mechanism that suppresses mitophagy in hepatocytes during steatosis has yet to be fully elucidated.

RING finger protein 31 (RNF31), sometimes referred to as HOIL-1 interacting protein (HOIP), is classified as an E3 ubiquitin ligase that falls under the category of RING-between-RING (RBR) proteins. RNF31 has a crucial role as a constituent of the linear ubiquitin chain assembly complex (LUBAC) [10]. Recent research has indicated that the main ubiquitin ligases RNF31/HOIP and OTULIN of LUBAC have a collective role in regulating autophagy initiation and maturation. This is achieved by their control of the linear ubiquitination and stability of autophagy-related protein 13 (ATG13) [11]. Furthermore, it has been observed that RNF31 can degrade A20, hence influencing the inflammatory response and the process of hepatocyte apoptosis that is mediated by the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-κB (NF-κB) signaling pathway [12]. Nevertheless, the precise modifications of RNF31 and its related pathways in the process of mitophagy remain poorly comprehended. Moreover, there is a need for further investigation to determine the role of RNF31 in the regulation of NAFLD pathogenesis and its potential as a therapeutic target for the treatment of NAFLD.

The current work presents novel findings indicating that RNF31 plays a crucial role as a BNIP3-dependent active factor in the regulation of mitophagy and the suppression of lipid accumulation in hepatocytes. The process by which RNF31 facilitates the attachment of ubiquitin molecules to the p53 protein promotes the maintenance of mitochondrial stability through a kind of cellular degradation known as BNIP3-related mitophagy. This eventually leads to the improvement of both mitochondrial and liver function in individuals with NAFLD. Additionally, it was shown that extracellular vesicles (EVs) generated from mesenchymal stem cells (MSCs) and containing RNF31 were able to efficiently decrease hepatic lipid accumulation and reinstate liver functionality in mice with NAFLD. The aforementioned findings provide a new approach for the therapeutic targeting of RNF31 in the management of NAFLD.