Nonalcoholic fatty liver disease (NAFLD) has become the leading chronic liver disease over the last decade, currently affecting 25~30% of the population worldwide. Nonalcoholic steatohepatitis (NASH) is the advanced stage of NAFLD and occurs when fat buildup causes inflammation and damage to the liver, which can progress to fibrosis, cirrhosis, and end-stage liver. NASH substantially increases disease morbidity and mortality [1]. Up to date, there is not any effective therapeutic method for this disease. The main therapeutic strategies are early identification of NASH, lifestyle intervention, and disease surveillance. Furthermore, liver biopsy remains the clinical standard for diagnosis, prognosis, and monitoring treatment response in NASH, and reliable non-invasive predictive biomarkers of NASH are urgently needed as well [2].

Ribonuclease L (RNase L) is an interferon (IFN)-inducible enzyme, functioning in the 2'-5' linked oligoadenylates (2-5A)/RNase L system of IFN against viral infection and cell proliferation [3]. Tissue distribution analysis revealed that RNase L is highly expressed in the spleen, thymus and immune cells such as macrophages, suggesting a role of RNase L in the immune system [4]. Indeed, in our previous study, we have demonstrated that RNase L mediates macrophage function through regulating the expression of pro- and anti-inflammatory genes under the stimulation with liposaccharide (LPS), which is independent of its nuclease activity through activating the toll-like receptor 4 (TLR4) signaling pathway [5]. It has been also reported that RNase L in immune cells activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome during viral infection [6]. Previously, we have revealed that RNase L functions as an essential regulator of adipogenesis and controls terminal adipocyte differentiation and lipids storage [7]. It has been well established that disrupted lipid homeostasis is a major cause of NAFLD. Thus, we investigated the role of RNase L in the pathogenesis of NAFLD.

In our study, we fed RNase L WT and KO mice with a high fat high cholesterol diet (HFHCD) for different times and investigated the role of RNase L in the development of NAFLD and the progression of NASH by monitoring the body weight gain, analyzing the biochemical parameters and immune factors, performing complete blood count (CBC) and evaluating the histological alterations in the livers. The results revealed that RNase L contributed to the development of NAFLD, which further progressed to NASH in a time-dependent fashion under the condition. WT mice showed significantly more severe NASH, evidenced by widespread macro-vesicular steatosis, hepatocyte ballooning degeneration, inflammation, and fibrosis, although physiological and biochemical data indicated that both types of mice developed obesity, hyperglycemia, hypercholesterolemia, dysfunction of the liver, and systemic inflammation at different extents. Further investigation demonstrated that RNase L was responsible for the expression of some key genes in lipid metabolism, inflammation, and fibrosis signaling.

In summary, understanding the progression of NAFLD from simple hepatic steatosis to NASH has important physiological and clinical implications. Our results suggest that RNase L may be a novel target for both diagnosis and treatment of NASH although more studies are needed for further investigating the role of RNase L in the pathogenesis of this disease.


  1. Sheka, A.C.; Adeyi, O.; Thompson, J.; Hameed, B.; Crawford, P.A.; Ikramuddin, S. Nonalcoholic Steatohepatitis: A Review. JAMA 2020, 323, 1175-1183, doi:10.1001/jama.2020.2298.
  2. Ratziu, V.; Francque, S.; Sanyal, A. Breakthroughs in therapies for NASH and remaining challenges. J Hepatol 2022, 76, 1263-1278, doi:10.1016/j.jhep.2022.04.002.
  3. Zhou, A.; Hassel, B.A.; Silverman, R.H. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell 1993, 72, 753-765, doi:10.1016/0092-8674(93)90403-d.
  4. Zeng, C.; Yi, X.; Zipris, D.; Liu, H.; Zhang, L.; Zheng, Q.; Malathi, K.; Jin, G.; Zhou, A. RNase L contributes to experimentally induced type 1 diabetes onset in mice. J Endocrinol 2014, 223, 277-287, doi:10.1530/joe-14-0509.
  5. Wei, R.; Chen, G.; Algehainy, N.; Zeng, C.; Liu, C.; Liu, H.; Liu, W.; Stacey, D.; Zhou, A. RNase L Is Involved in Liposaccharide-Induced Lung Inflammation. Viruses 2020, 12, doi:10.3390/v12010073.
  6. Chakrabarti, A.; Banerjee, S.; Franchi, L.; Loo, Y.M.; Gale, M., Jr.; Núñez, G.; Silverman, R.H. RNase L activates the NLRP3 inflammasome during viral infections. Cell Host Microbe 2015, 17, 466-477, doi:10.1016/j.chom.2015.02.010.
  7. Fabre, O.; Salehzada, T.; Lambert, K.; Boo Seok, Y.; Zhou, A.; Mercier, J.; Bisbal, C. RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation. Cell Death Differ 2012, 19, 1470-1481, doi:10.1038/cdd.2012.23.