LincRNA-p21: A Double-Edged Sword in Ethanol-Induced Liver Damage and Its Nanoparticle Solution

Shun Wang,1 Zhao-Chao Nie,1 Yang Liu,2 Zhi-Yue Zhang,2 Yi-Min Feng,1 Chengwei Wang,3 Jun Jiang3 1Department of Clinical Laboratory, The Second Qilu Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China; 2NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 3Department of Neurosurgery, The Second Qilu Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of ChinaCorrespondence: Jun Jiang, Department of Neurosurgery, The Second Qilu Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China, Email [email protected] Chengwei Wang, Department of Neurosurgery, The Second Qilu Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China, Email [email protected]: Background: Alcohol-related liver disease (ALD) is the leading cause of liver disease-related deaths globally, necessitating new treatments. This study investigates the role of long intergenic noncoding RNA (lincRNA)-p21 in ALD and explores therapeutic strategies for liver injury.Methods: We identified lncRNAs linked to ethanol-induced liver injury using the Gene Expression Omnibus (GEO) database. Experiments were conducted to assess the function of lincRNA-p21 in ALD both in vivo and in vitro. Autophagy was analyzed through electron microscopy, autophagic flow, and protein expression. Bioinformatics explored underlying mechanisms, focusing on m6A modification of lincRNA-p21 by ALKBH5 using RNA Immunoprecipitation (RIP) and meRIP-PCR. Ferroptosis was induced with erastin, and its levels were measured by cell ROS and viability. A nanoplatform-based system was developed to co-deliver a plasmid encoding lincRNA-p21 and a ferroptosis inhibitor. We developed a nanoplatform-based co-delivery system to deliver a plasmid encoding lincRNA-p21 and the ferroptosis inhibitor ferrostatin-1 (ferr-1/lincRNA-p21@NP) to the liver.Results: LincRNA-p21 protected liver cells against ethanol-induced injury by promoting autophagy. ALKBH5 mediated the m6A demethylation and lincRNA-p21 upregulation. However, we revealed a dual-edged sword function for lincRNA-p21 in ethanol-induced liver injury in mice. LincRNA-p21 reduced acute ethanol-induced cell injury by enhancing autophagy but exacerbated chronic ethanol-induced liver cell injury by increasing ferroptosis. In vivo and in vitro analyses showed favorable therapeutic effects of ferr-1/lincRNA-p21@NPs on ALD.Conclusion: These results show that lincRNA-p21 affects autophagy and ferroptosis, and the ferr-1/lincRNA-p21@NP nanosystem can provide protection against ALD. Keywords: alcoholic liver disease, LincRNA-p21, autophagy, ferroptosis, drug delivery systems