The liver, as the largest solid organ in the human body, plays a crucial role in various physiological processes, including substance metabolism, energy metabolism, immune response, blood volume regulation, and hormone regulation [1]. However, various factors such as viral infections, exposure to aflatoxin, drug reactions, and nutritional excess can lead to liver dysfunction or even failure. Currently, liver diseases have become a global health issue that poses a significant threat to human well-being. Multiple studies [2-4] have found that ferroptosis is involved in the occurrence and progression of various liver diseases. This suggests that targeting ferroptosis could be a novel direction for the treatment of liver diseases.

Dolma [5] and Yang [6], in 2003 and 2008 respectively, discovered that erastin and RSL3 have selective cytotoxic effects on cancer cell lines with RAS gene mutations. This type of cell death process is different from apoptosis as it lacks typical apoptotic features such as mitochondrial cytochrome c release, caspase activation, and chromatin fragmentation. It cannot be blocked by caspase inhibitors but can be inhibited by iron chelators (such as deferoxamine mesylate) and antioxidants (such as vitamin E). Therefore, Dixon et al. [7] proposed the concept of ferroptosis in 2012 to distinguish it from other forms of selective cell death.

Ferroptosis can be classified into two pathways based on the inducing factors: exogenous and endogenous pathways [8]. The exogenous pathway refers to the initiation of ferroptosis by inhibiting cell membrane transport proteins (such as the cystine/glutamate antiporter) or activating serum transferrin and lactoferrin to transport iron into the cells. The endogenous pathway primarily involves the initiation of ferroptosis by inhibiting the activation of intracellular antioxidant enzymes, such as glutathione peroxidase 4 (Gpx4). In essence, it is an outcome where the dynamic balance between intracellular oxidative damage and oxidative defense is disrupted [9]. The former is characterized by the accumulation of reactive oxygen species (ROS) caused by iron overload, while the latter is characterized by a decrease in the activity of the enzyme GPX4. Ultimately, this leads to lipid peroxidation.

Iron Overload Leads to The Accumulation Of ROS

In cells, there are several pathways that can promote an increase in intracellular Fe2+ levels, such as enhancing iron uptake, reducing intracellular iron efflux, and promoting intracellular iron release [10]. It is manifested in the binding of serum transferrin to transferrin receptors [6], the entry of lactoferrin into the cell through integrin endocytosis [11], heme enters the cell through solute carrier superfamily members FLVCR2[12], SLC48A1[13]and SLC46A1[14], and nuclear receptor coactivator 4 (NCOA4) binds to ferritin heavy chain subunit (FTH1) to promote ferritin autophagic decline solution [15, 16]. Excess iron can produce a large number of reactive oxygen species ROS through the fenton reaction on the one hand, and activate iron-containing enzymes (such as lipoxygenase ALOXS) on the other hand [17, 18]. Polyunsaturated fatty acids (PUFAs), under the action of acyl-CoA synthetase long-chain family member 4 (ACSL4) and Lysolecithin acyltransferase 3 (LPCAT3), may form polyunsaturated fatty acid phospholipids (PUFA-PL) with phospholipids on the membrane. Eventually, lipid peroxidation occurs through the interaction of ALOXS and ROS, leading to membrane structural damage and functional impairment. It is worth noting that iron overload does not necessarily lead to ferroptosis, as this outcome depends on the oxidative state of iron and the specific cellular environment [19]. Ferroptosis mainly involves specific lipid oxidation, and different lipid oxidation has different promoting ability to ferroptosis. The free PUFA itself is not the driver of ferroptosis, but PUFA-PL is. The destruction of membrane structure is not only limited to mitochondria, but also exists in the plasma membrane, and the rupture of the plasma membrane is the manifestation of late ferroptosis [20, 21]. Endoplasmic reticulum [22], peroxisome [23], lysosome [24] and golgi apparatus[25] all participate in this process. Correspondingly, iron output mediated by SLC40A1[26] and prominin2 stimulate the formation of exosomes containing ferritin [27] among the ways of reducing the intracellular Fe2+ content. 

GPX4 Enzyme Activity Decreased

The xc− system is a heterodimer composed of SLC7A11 and SLC3A2 connected by disulfide bonds, which can reverse transport extracellular cysteine to intracellular glutamate in a ratio of 1:1[28]. The cystine that enters the cell is first oxidized to cysteine, and then glutathione (GSH) is synthesized under the catalysis of glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS). Glutathione peroxidase (Gpx4) reduces lipid peroxide to non-toxic lipid alcohols with the help of GSH, thereby inhibiting ferroptosis [29]. In addition to Gpx4 pathway, there are also three non-GPX4 pathways: AIFM2-CoQ10 pathway [20, 21], GCH1-BH4 pathway [30] and ESCRT-III membrane repair system [31]. Moreover, there is a synergistic relationship between them. For example, AIFM2 can prevent ferroptosis in cancer cells by activating ESCRT-III membrane repair system in addition to regulating the production of CoQ10 [32].

Liver disease is a general term for all diseases occurring in the liver, including common fatty liver, viral hepatitis, drug-induced liver injury, cirrhosis, liver cancer and so on. Although there are many corresponding treatment methods, the overall curative effect is not ideal, which seriously affects people's quality of life. Studies have shown that ferroptosis plays an important role in the occurrence and development of many liver diseases, which may be a new therapeutic breakthrough [33-35].

Alcoholic Liver Disease, ALD

ALD refers to a class of liver diseases caused by long-term heavy drinking, including alcoholic fatty liver, alcoholic hepatitis, cirrhosis and its complications. Habitual drinking can promote Fe2+ accumulation by up-regulating the expression of transferrin receptor in hepatocytes [36, 37]. Liu [3] found that alcohol induced hepatocyte injury by decreasing SLC7A11 and Gpx4 expression in both L-02 human normal hepatocytes in vitro and in vivo mouse models, and that ferrostatin-1 could reverse the above changes, suggesting that targeting ferroptosis may be a therapeutic approach for ALD.

Non-Alcoholic Fatty Liver Disease, NAFLD

NAFLD is a chronic progressive liver disease with steatosis as its main pathological feature, including simple fatty liver and non-alcoholic steatohepatitis, which can develop into cirrhosis and liver cancer [38, 39]. NAFLD is the most common chronic liver disease in the world today, and its incidence in Europe and America has reached more than 20% [40]. At present, it is generally believed that the pathogenesis of NAFLD is related to inflammation, oxidative stress, insulin resistance, lipid metabolism disorder, endoplasmic reticulum stress and other factors [41]. Tsurusaki [2] constructed a mouse model of steatohepatitis using choline deficiency/ethionine supplemented diet, and found that rosiglitazone, an inhibitor of ACSL4, soluble vitamin E, and iron complex agent deferoxamine could inhibit liver cell death, inhibit immune cell penetration, and reduce inflammatory cytokines. It is suggested that ferroptosis is involved in the process of liver cell death in steatohepatitis. Thymosin β4 (Tβ4) is a multifunctional peptide that is widely present in various nucleated cells. It has been shown to reduce the levels of reactive oxygen species (ROS) in cardiac microvascular endothelial cells during myocardial ischemia-reperfusion [42]. Research has found that the serum levels of Tβ4 are decreased in patients with NAFLD [43]. Zhu [44] found in vivo and in vitro experiments that Tβ4 upregulates the expression of Gpx4, thereby inhibiting ferroptosis and reducing oxidative stress and lipid peroxidation in the liver. This further leads to a decrease in the recruitment of inflammatory factors and activation of cell apoptosis signaling pathways in the liver.

Hepatitis C

Hepatitis C virus is a highly pathogenic RNA virus. Unlike other hepatitis viruses, it has the ability to establish persistent infection in the human body [45]. Although direct-acting antiviral drugs targeting the replicase of hepatitis C virus (HCV) can effectively treat HCV infection, there is still a 5% occurrence of treatment-resistant infections in patients [46]. Yamane [45] found that aldehydes generated from lipid peroxidation can bind to the transmembrane region of the Hepatitis C virus replicase, altering the conformation of the replicase and reducing its enzymatic activity. This leads to the inhibition of viral replication. Indeed, this mechanism may contribute to the ability of the Hepatitis C virus to establish persistent infection by limiting its exposure to the immune system and providing opportunities for continuous replication. Yamane [4] found that fatty acid desaturase 2 (FADS2) is the first rate-limiting enzyme in the biosynthesis of highly unsaturated fatty acids. They discovered that FADS2 promotes lipid peroxidation, which inhibits the replication of hepatitis C virus. However, it also increases the sensitivity of cells to ferroptosis. Promoting FADS2 expression or enhancing its biological function through targeting FADS2 could be a novel approach for treating hepatitis C virus infection. However, it is important to strike a balance in promoting liver cell Ferroptosis. Careful consideration and further research are needed to optimize this potential therapeutic strategy.

Drug-Induced Liver Injury, DILI

DILI is a relatively common liver disease that can occur after exposure to various drugs, herbs, and dietary supplements. The damage to the body varies greatly, ranging from mild elevation of aminotransferase to acute liver failure within a few days, leading to death [47]. Acetaminophen (APAP) is a commonly used over-the-counter analgesic and antipyretic medication. However, excessive intake of APAP is a common cause of drug-induced liver injury. In the United States and some European countries, APAP is responsible for approximately 50% of cases of acute liver failure [48, 49]. After entering liver cells, a small portion of APAP can be metabolized by cytochrome P450 enzymes, primarily CYP2E1, into N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is a highly reactive metabolite that can rapidly react with glutathione (GSH), leading to significant depletion of GSH [50]. Based on this viewpoint, Lorincz [51] treated primary mouse liver cells cultured with APAP with ferrostatin-1 and found that it significantly improved cell viability. This confirmed that ferroptosis may be involved in APAP-induced cell death in primary liver cells. However, there were no significant changes observed in the expression of CYP2E1 and GSH, suggesting the existence of other molecular mechanisms. Jollow[52] found that APAP can induce changes in mitochondrial ultrastructure and function. This suggests that mitochondria may play an important role in APAP-induced ferroptosis in primary liver cells. Voltage-dependent anion channels (VDAC) control the transport of metabolites and ions between mitochondria and the cytoplasm. They also regulate the production of reactive oxygen species (ROS). Under the stimulation of apoptotic factors, VDAC assembles into oligomers, including dimers, trimers, and tetramers, forming pores on the outer mitochondrial membrane [53]. It has been shown to be a new target of ferroptosis inducer erastin [54]. Lange [55] found that iron ions may enter the intermembrane space of mitochondria through the VDAC located in the outer mitochondrial membrane. Niu [56] used APAP to treat primary mouse liver cells and found that VDAC oligomerization was intensified, leading to mitochondrial iron overload, accumulation of reactive oxygen species (ROS), and loss of membrane potential. Additionally, metabolites associated with the tricarboxylic acid cycle, such as citrate, succinate, and malate, were significantly reduced. On the other hand, the VDAC oligomerization inhibitor VBIT-12 can significantly reverse these changes, indicating that mitochondria can participate in APAP-induced drug-induced liver injury through VDAC-mediated Ferroptosis in liver cells.

Autoimmune Hepatitis, AIH

The characteristics of AIH include inflammation, the presence of autoantibodies, elevated levels of gamma globulins, and interface Hepatitis [57]. Zhu [58] established an AIH mouse model using S100 liver antigen and found that the mice exhibited multi-zone inflammatory necrosis, increased lymphocyte infiltration, and disrupted liver tissue structure. Additionally, they observed upregulation of cyclooxygenase-2 (COX-2) and ACSL4 protein levels, as well as downregulation of Gpx4 and FTH1 expression. These changes can be reversed by ferrostatin-1, suggesting that Ferroptosis occurs in S100-induced autoimmune hepatitis. The nuclear factor erythroid associated factor 2 (Nrf2) is a transcription factor that plays a key role in antioxidant reaction [59, 60]. During oxidative stress, Nrf2 dissociates from a Kelch-like ECH-associated protein heterodimer in the cytoplasm and migrates to the nucleus, where Nrf2 interacts with antioxidant response elements to trigger transcription of target genes (such as HO-1) to alleviate oxidative stress [61]. Zhu [58] found that Nrf2/HO-1 signaling pathway may play a key role in inhibiting Ferroptosis.

Acute Liver Failure, ALF

ALF is a severe hepatocyte injury syndrome characterized by rapid increase of aminotransferase and coagulation disorder, with sudden onset and high mortality [62]. Hepatitis B virus infection is one of the main causes, resulting in a lower ALF survival rate, but unfortunately, the specific mechanism of hepatitis B virus causing ALF is not clear [63]. HBx is a regulatory protein of hepatitis B virus, which plays an important role in the occurrence and development of liver fibrosis, hepatocellular carcinoma, ALF and other serious liver diseases [64-66]. Guo [67] established ALF models in vivo and in vitro by using LPS/D-galactosamine on mice and D-galactosamine on mouse primary hepatocytes, and found that the survival rate of mice and hepatocytes decreased, GPX4 and GSH expression decreased, and ROS increased, suggesting that ferroptosis may be involved in ALF. It was found that HBx can promote the trimethylation of histone H3 lysine 27(H3K27) by stabilizing EZH2 (a histone methyltransferase), thereby inhibiting the expression of SLC7A11 in hepatocytes and accelerating Ferroptosis.

Hepatocellular Carcinoma, HCC

Primary liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide, of which HCC accounts for 75%-85% [68]. Unfortunately, more than 50% of patients are diagnosed at an advanced stage [69]. For patients with advanced liver cancer, sorafenib is the only approved systemic therapy that improves overall survival [70]. Studies have shown that sorafenib, compared with other kinase inhibitors, can prevent SLC7A11 from mediating cystine into the cell and effectively promote ferroptosis [71]. However, the overall effect was limited, suggesting the possibility of drug resistance [72]. YAP/TAZ is a transcriptional effector of the Hippo signaling pathway. Gao [73] found that YAP/TAZ induced the expression of SLC7A11 in a tead dependent and ATF4 dependent manner, and reduced the effect of sorafenib on promoting Ferroptosis in HCC.

Since the discovery of ferroptosis, a large number of researchers have invested in the research of ferroptosis one after another, intending to clarify ferroptosis from the perspectives of morphology, biochemical characteristics and intrinsic molecular mechanisms, eager to obtain new methods for the treatment of diseases and achieve curve overtaking. However, ferroptosis is a double-edged sword because it is involved in multiple physiological and pathological processes and plays different roles in different pathological conditions. For example, in hepatocellular carcinoma, promoting ferroptosis can kill cancer cells, but in NAFLD, inhibiting ferroptosis can rescue damaged liver cells. Therefore, it is necessary to understand the specific role of ferroptosis in different physiological and pathological processes, so as to regulate ferroptosis selectively.

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