Nonalcoholic fatty liver disease (NAFLD) encompasses various conditions such as simple fatty liver disease (SFL), nonalcoholic steatohepatitis (NASH), cirrhosis, and liver fibrosis [1]. NAFLD is characterized by autophagy, hepatocyte apoptosis, and subsequent collagen deposition, recently also known as metabolic dysfunction-associated steatotic liver disease (MASLD) [2]. Hepatocyte autophagy and apoptosis are affected by metabolic reprogramming, where the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family is vital [3]. Indeed, a dysregulated ENPP family may impair cellular functions, including autophagy and apoptosis. However, the molecular mechanisms of the ENPP family in NAFLD and hepatocyte phenotypes remain poorly understood at the molecular level.

Currently, little is known about the roles of ENPP family genes in NAFLD. ENPP family members (ENPP1-7) have been implicated in key biological and pathophysiological processes, including nucleotide [4] and phospholipid signaling [5], fibrotic diseases [6], and tumor-associated immune cell infiltration [7]. Ecto nucleotide pyrophosphate (ENPP1) is an energy metabolism factor crucial in lipid metabolism disorders [8]. ENPP1 plays an important role in heart physiology and pathology by regulating various crucial cellular events, including autophagy and differentiation [9]. Similar to heart disease, NAFLD exhibits abnormal autophagic characteristics. However, whether ENPP1 regulates hepatocyte phenotype, thereby regulating NAFLD liver fibrosis, is yet to be determined.

The dysregulation of ENPP1 expression may be linked to epigenetic mechanisms. TET proteins belong to a novel class of DNA demethylases that oxidize 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5hmC), which is subsequently converted into unmethylated cytosine [10]. Although much is known about the role of TETs in cancer development [11], little is known about their function and mechanism in NAFLD liver fibrosis, despite the altered expression of TETs having been noted in fibrotic liver diseases [12]. This study makes a novel contribution to the literature by describing how ENPP1 expression and TET3 are related and how they may lead to NAFLD liver fibrosis and hepatocyte autophagy.

This study aimed to find how ENPP1 expression is involved in NAFLD liver fibrosis and the precise mechanism between TET3 and ENPP1 in hepatocyte autophagy.