Arsenic Trioxide (ATO, As2O3) has been employed as chemotherapy to treat the relapsed or refractory type of acute promyelocytic leukemia (APL) and various hematopoietic malignancies since its initial use in the 1970s; with its efficacy demonstrated in clinical trials [1]. APL is a distinct subtype of acute myelogenous leukemia; constituting 10 to 15 % of adult patients with myeloid leukemia. ATO is administered via intravenous infusions daily for 28–42 days; resulting in complete APL remission [2]. ATO is the most effective monotherapy in APL management; elevating patient life expectancy to 80 to 90 % when concurrently treated with ATO and all-trans retinoic acid. However, ATO administration has been associated with adverse effects on various organs; particularly the liver [3], [4], [5], [6].

The liver serves as the primary organ responsible for eliminating toxins and drugs; however, these toxic substances can also inflict harm upon it [7]. Consequently, the liver stands as the primary organ susceptible to pathological oxidative stress cascades [8]. Previous findings have unveiled that oxidative stress and an disrupted redox status represent the primary mechanisms by which ATO induces hepatotoxicity [9]. Following ATO administration, various reactive oxygen species (ROS) are unleashed, resulting in an imbalance of the redox status and the depletion of endogenous antioxidants, such as superoxide dismutase (SOD) and glutathione (GSH). This depletion leads to the excessive accumulation of ROS, lipid peroxidation, irreversible damage to proteins and DNA, and further hepatocellular injury [10], [11].

The hepatotoxicity induced by ATO can also be attributed to the activation of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin 1-β (IL-1β), and interleukin-6 (IL-6). Proinflammatory activity may arise as a response to oxidative stress or as a direct effect of ATO [12], [13]. When cellular antioxidant defenses are overwhelmed, ROS-induced damage to cells leads to necrosis or apoptosis, as evidenced by the presence of oxidative stress and inflammation.

MiR-122 is among the noncoding microRNAs that are overexpressed in damaged hepatocytes, and its expression correlates with the severity of damage [14]. Furthermore, hepatocellular damage can lead to the overexpression of miR-21 in the liver through an mTOR-dependent pathway, resulting in the inhibition of phosphatase and tensin homolog levels (PTEN) [15]. The increased insult to the liver triggers the activation of the autophagy process within hepatic tissue, aimed at eliminating damaged cells and organelles [16], [17]. LC3 plays a crucial role in initiating the autophagy process, undergoing degradation into microtubule-associated protein light chain 3 (LC3-II), ultimately leading to total proteolysis [18].

Dapagliflozin (DPG) belongs to the class of sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors), which are oral antihyperglycemic medications. DPG exerts its blood glucose-lowering effects by promoting urinary glucose excretion, leading to reduced glycated hemoglobin levels, and it also influences beta cell function and insulin sensitivity [19]. Recent studies have highlighted the therapeutic potential of DPG in the treatment of non-alcoholic fatty liver, with observed improvements in liver histology and the modulation of fibroblast growth factor-21 levels [20], [21]. Emerging research has unveiled the multifaceted role of DPG, expanding beyond its anti-hyperglycemic properties to encompass the regulation of various oxidative and inflammatory pathways. These properties include its ability to provide gastroprotection against gastric lesions, alleviate Alzheimer's disease models, and enhance recovery from acute renal injury [22], [23], [24]. This wide-ranging spectrum of actions positions DPG as a promising candidate for the treatment of various disorders. Nevertheless, some studies have suggested that the effects of DPG may be attributed to its glucose-lowering actions in addition to its anti-inflammatory and anti-fibrotic impacts [25], [26].

In the present study, the authors sought to investigate the molecular and toxicological pathways underlying the effects of ATO on the liver. Furthermore, the study aimed to explore the potential protective effects of DPG on hepatic tissue against ATO-induced toxicity.