Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, with its global incidence keeps growing attributed to the rising epidemic of obesity and diabetes 1, 2, 3. It comprises a spectrum of liver disorders that range from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) [4]. The pathological progression of NAFLD is characterized by excessive lipid accumulation in the liver and impaired lipid metabolism 5, 6. While liver steatosis in early stage is reversible, NASH has the potential to develop into advanced liver diseases such as cirrhosis and hepatocellular carcinoma (HCC) [7]. Therefore, elucidating the underlying molecular mechanisms of NASH will provide a therapeutic strategy for patients with steatohepatitis.

Telomeric repeat-binding factor 2-interacting protein 1 (Terf2ip), also known as a repressor and activator protein, is a component of the shelterin complex that has been shown to bind to telomeric repeats through interaction with telomeric repeat-binding factor 2 (TRF2) [8]. Besides, Terf2ip played an essential role in telomere recombination and homology-directed repair [9]. In addition to being a protective complex at telomeres, Terf2ip was also known for its nontelomeric functions. Recent studies have identified Terf2ip as a regulator of the NF-κB signaling pathway in various inflammatory models 10, 11. Our previous research demonstrated that Terf2ip accelerated liver ischemia reperfusion injury by mediating innate proinflammatory responses [12]. Furthermore, Terf2ip has been shown to protect against diet-induced obesity through PPARα and PGCα pathway [13]. However, the impact of Terf2ip on hepatic inflammation and steatohepatitis during the pathogenesis of NASH remains unclear.

Autophagy, a catabolic process, serves to degrade cellular proteins and damaged organelles, thereby providing an energy source and maintaining cell homeostasis 14, 15. Lipophagy, a specialized form of autophagy, selectively recognizes lipid droplets, degrading triglycerides and releasing free fatty acids, thereby contributing to fatty acid metabolism [16]. Accumulating evidence suggests a critical role of lipophagy in the progression of NASH. In diet-induced steatohepatitis, activated lipophagy has been reported to improve lipid metabolism and suppress inflammatory responses through the removal of reactive oxygen species production [17]. Besides, recent studies have indicated impaired autophagic flux in the livers of patients with NAFLD or NASH 18, 19. These findings revealed the potential therapeutic target of enhancing lipophagy in the treatment of NASH.

In this study, our aim was to elucidate the function and mechanism of Terf2ip in the progression of NASH. We observed a significant down-regulation of Terf2ip in the livers of patients with NASH and in mice NASH models. Additionally, Terf2ip deficiency was associated with impaired autophagy and FAO in mice with steatohepatitis induced by HFD or MCD. Interestingly, we discovered that Terf2ip bound to the promoter region of Sirt1, thereby regulating autophagy levels. Re-expression of Terf2ip in NASH models alleviated hepatic steatosis, inflammation, and restored autophagy. In summary, our findings highlighted that Terf2ip deficiency promoted the progression of NASH through activating the Sirt1/ AMPK pathway.