Hepatic ischemia–reperfusion injury (IRI) is a condition characterized by liver damage resulting from the interruption and subsequent restoration of blood flow to the liver. This condition commonly occurs in various clinical contexts, including liver transplantation, major hepatic surgery, and ischemic liver diseases [1]. Hepatic IRI can significantly compromise liver function, leading to complications that extend beyond the immediate postoperative phase. Clinically, the deterioration of liver function in response to hepatic IRI may contribute to increased postoperative morbidity and extended hospital stays. Furthermore, the long-term consequences of hepatic IRI may play a role in the development of chronic liver diseases, emphasizing the need for a comprehensive understanding of the underlying regulatory mechanisms. An in-depth understanding of the regulatory mechanisms governing hepatic IRI is of paramount importance, as it paves the way for the development of therapeutic strategies aimed at mitigating liver damage during the perioperative period. The complex interplay of signaling pathways and molecular mediators involved in hepatic IRI underscores the significance of research efforts aimed at unraveling these intricate mechanisms.

The pathophysiology of hepatic IRI entails an intricate interplay of cellular and molecular events. During the ischemic phase, the absence of oxygen and nutrients leads to disrupted cellular metabolism and heightened accumulation of detrimental metabolites. Subsequent reperfusion generates an abundance of reactive oxygen species (ROS), instigating mitochondrial dysfunction and setting off a chain of inflammatory responses. These responses further intensify the damage to hepatocytes, inflammation, and cell death [2]. In recent years, the scientific community has shown an increasing interest in the pivotal role of specific molecules and signaling pathways contributing to the progression of hepatic IRI. Among these pathways, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as a central player in the innate immune response, responsible for detecting cytosolic DNA and initiating immune reactions against microbial infections and cellular stress [3]. During hepatic IRI, mitochondria are particularly susceptible to damage, leading to the release of mitochondrial DNA (mtDNA) into the cytoplasm [4]. Within this context, cGAS, as a prominent member of DNA recognition receptors, plays a pivotal role in identifying and binding to damaged mtDNA. This binding event triggers self-activation, culminating in the initiation of downstream signaling pathways by promoting the synthesis of cyclic GMP-AMP (cGAMP). Subsequently, cGAMP associates with STING localized within the endoplasmic reticulum. This association leads to STING phosphorylation and its translocation to the Golgi apparatus, forming a STING complex. This complex, in turn, recruits and phosphorylates TANK-binding kinase 1 (TBK1), which activates the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3). IRF3 promotes the transcription and release of type I interferon (IFN-I), a key mediator in the immune response. An expanding body of research indicates the involvement of the cGAS-STING pathway in Hepatic IRI [5]. Activation of this pathway within hepatocytes leads to the production of pro-inflammatory cytokines and chemokines, thereby fostering the recruitment of immune cells and exacerbating liver injury during hepatic IRI. Inhibiting this pathway has shown promise in attenuating the inflammatory response and protecting against liver damage [6].

In the intricate landscape of mitochondrial regulation and hepatocyte resilience to damage, the Sirtuin family of proteins emerges with diverse roles attributed to its seven distinct members [7]. Among these, Sirtuin 3 (Sirt3) emerges as a principal mitochondrial deacetylase, pivotal for its specific role in regulating mitochondrial metabolism and protecting against oxidative damage. Understanding the distinct functions of sirtuins is imperative for delineating the unique contribution of Sirt3. Whereas Sirt1 is predominantly nuclear and influences processes such as DNA repair and metabolic regulation, Sirt4 and Sirt5 exert regulatory roles in amino acid metabolism and mitochondrial function but do not exhibit the same level of influence on mitochondrial oxidative stress responses as does Sirt3 [8]. Furthermore, Sirt3 is unique among sirtuins in its ability to deacetylate and activate key metabolic enzymes including superoxide dismutase 2, which is central to the detoxification of ROS within mitochondria. Given the critical role of mitochondrial dysfunction and resultant oxidative stress in hepatic IRI, our focus on Sirt3 is underscored by its prominent influence on these processes [9]. Moreover, studies have indicated that Sirt3 deficiency exacerbates IRI, which is not as clearly established for other sirtuin proteins [10]. This specificity pivots on the role of Sirt3 as a critical mediator of mitochondrial integrity and an indirect regulator of inflammatory responses, extending beyond its metabolic functions [11]. Activation of Sirt3 has been demonstrated to reduce ROS production, inhibit apoptosis, and enhance mitochondrial function, thereby ameliorating liver damage in hepatic IRI [12]. Notably, Sirt3 possesses robust deacetylation activity and engages in the epigenetic modification of crucial proteins. Furthermore, Sirt3 governs gene transcription by facilitating the nuclear translocation and phosphorylation of various downstream targets, including transcription factors Sp1, Pu1, and p65. All these factors have been previously implicated in oxidative stress responses [13]. Despite the expanding knowledge on the intricacies of hepatic IRI and the roles of Sirt3 and the cGAS-STING pathway, the precise regulatory mechanisms through which Sirt3 influences the cGAS-STING pathway remain incompletely understood. This study focused on exploring the crucial roles of Sirt3 and the cGAS-STING pathway, and further discussed the regulatory mechanisms of Sirt3 on the cGAS-STING pathway, which may lead to novel treatment approaches for hepatic IRI and improved clinical outcomes.