ORTHOTOPIC liver transplantation (OLT) is regarded as the most effective treatment option for patients with end -stage liver disease or hepatocellular carcinoma [1]. However, liver transplantation can also be accompanied by an increased risk of ischemia-reperfusion injury (IRI). IRI remains a danger-ous risk factor for acute and chronic rejection and a leading cause of organ shortages. The graft needs to go through a series of processes, including acquisition, preservation, and implanta-tion, among which preservation is the key stage to reduce IRI [2]. At present, the most widely used method is static cold pres-ervation with University of Wisconsin (UW) solution or CUS-TODIOL HTK Solution (Dr. Franz Koehler Chemie). Theoretically, the graft can be stored for 20 to 24 hours [3]. However, it has been found that the incidence of bile duct com-plications in OLT will be higher if the cold ischemia time is greater than 13 hours [4], among which IRI of bile duct epithe-lial cells is a major factor for postoperative nonanastomotic bili-ary strictures [5]. As a result, IRI has become one of the stickiest problems in transplantation, so innovative strategies to fight against IRI are desperately needed to improve the out-comes of OLT and expand the donor organ pool [6].Cell junctions are mainly divided into gap junctions (GJs), tight junctions (TJs), adherens junctions, and desmo-somes. GJs are widely present in various tissues and consist of connexons on the membranes of two adjacent cells. Each connexon contains six identical or different connexins (Cx). GJs allow the direct transfer of electrical charge and mole-cules, which is commonly deemed to be the integral basis of organ damage deterioration and magnification [7]. GJs play a critical role in maintaining homeostasis by participat-ing in cell growth, differentiation, and metabolism [8,9], as well as regulating oxidative stress and inflammation [10]. Cx43 is a widespread GJ protein that implements the transfer of molecules between cells at a higher efficiency than the constitutively expressed Cx26 and Cx32 [11]. According to existing reports, the liver would increase the expression of Cx43 as an adaptive protective response to intensify cell-to-cell communication [12]. TJ is an intercel-lular protein complex found on epithelial cells in all organs that is essential for the barrier function of epithelia [13]. Evidence from experimental studies shows that expression of TJ proteins is changed in hepatocellular carcinoma and cholangiocarcinoma [14]. These achievements prompt us to conceive whether influencing cell junctions and their pro-teins helps to reduce IRI.a-Connexin carboxyl terminal peptide 1 (ACT1) is a syn-thetic peptide containing 25 amino acids. It has the PDZ domain of Cx43, which can interact with the PDZ2 domain of ZO-1 [15]. Therefore, ACT1 can selectively restrain the protein -pro-tein interaction appearing between ZO-1 and Cx43 to promote the formation of GJs and strengthen the function of GJs [16]. Existing research shows that ACT1 can alleviate inflammation and promote the healing of chronic venous ulcer wounds by regulating Cx43 [17]. In addition, findings have emerged that ACT1 is detected to protect the endothelium from thrombin -induced disruption in cell-cell contacts in a ZO-1 interaction -associated manner [18]. These reports prompt us to quest whether ACT1 can also reduce IRI in OLT.