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• Skip to main content Advertisement Cell Death Discovery View all journals Search Log in Explore content About the journal Publish with us Sign up for alerts RSS feed nature cell death discovery review articles article Review Article Open access Published: 24 January 2024 Ferroptosis: Emerging mechanisms, biological function, and therapeutic potential in cancer and inflammation Xin Jin, Jiuren Tang, Xiangyu Qiu, Xiaoya Nie, Shengming Ou, Geyan Wu, Rongxin Zhang & Jinrong Zhu Cell Death Discovery volume 10, Article number: 45 (2024) Cite this article 10k Accesses 19 Citations 1 Altmetric Metricsdetails Abstract Ferroptosis represents a distinct form of programmed cell death triggered by excessive iron accumulation and lipid peroxidation-induced damage. This mode of cell death differentiates from classical programmed cell death in terms of morphology and biochemistry. Ferroptosis stands out for its exceptional biological characteristics and has garnered extensive research and conversations as a form of programmed cell death. Its dysfunctional activation is closely linked to the onset of diseases, particularly inflammation and cancer, making ferroptosis a promising avenue for combating these conditions. As such, exploring ferroptosis may offer innovative approaches to treating cancer and inflammatory diseases. Our review provides insights into the relevant regulatory mechanisms of ferroptosis, examining the impact of ferroptosis-related factors from both physiological and pathological perspectives. Describing the crosstalk between ferroptosis and tumor- and inflammation-associated signaling pathways and the potential of ferroptosis inducers in overcoming drug-resistant cancers are discussed, aiming to inform further novel therapeutic directions for ferroptosis in relation to inflammatory and cancer diseases. Similar content being viewed by others Ferroptosis: mechanisms, biology and role in disease Article 25 January 2021 Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies Article Open access 08 March 2024 Ferroptosis: A double-edged sword Article Open access 30 May 2024 Facts Ferroptosis represents a distinct iron-dependent form of cell death, and the process of cell death is usually accompanied by iron accumulation and lipid peroxidation. Ferroptosis is involved in the development of a variety of diseases, such as neurological disorders, tissue ischemia-reperfusion injury, and cancer. Ferroptosis has a dual effect on promoting and suppressing tumors in experimental tumor models. Ferroptosis inducer therapy is a promising new anticancer therapy. Open questions Inflammation has an impact on ferroptosis, but what precisely is the underlying mechanism? Whether definitive biomarkers of ferroptosis can be identified in the future could prove invaluable in studying the biological function of ferroptosis. Ferroptosis inducers may offer new therapeutic opportunities for many diseases, but their specific applications need to be further investigated. Introduction Ferroptosis, as proposed by Dixon in 2012, is an iron-dependent form of regulated cell death (RCD) that exhibits distinct morphological and biochemical features compared to other cell death forms [1]. The critical characteristics of ferroptosis are marked by iron accumulation and lipid peroxidation. Consequently, intracellular iron accumulation and lipid peroxidation are the primary drivers of ferroptosis occurrence [1]. Current cancer treatment strategies aim to selectively eliminate cancer cells without causing harm to healthy cells [2]. Traditional antitumor drugs are successful in killing tumor cells by triggering apoptosis. However, the ability of apoptosis to remove tumor cells is restricted, and these traditional therapies are susceptible to drug resistance [3]. Therefore, alternative methods of inducing non-apoptosis present new possibilities for treating tumors. Apoptosis is one of the most extensively researched regulated cell death forms [4]. As a unique RCD, ferroptosis has attracted much attention. Aberrant activation of ferroptosis pathways is a hallmark of various pathologies, such as malignancies and chronic inflammatory disorders. Recently, significant advancements have been achieved in exploring ferroptosis in cancer cells [3]. In addition, cancer-related signaling pathways can regulate ferroptosis in cancerous cells. Cancer cells display an exceptional neoplastic metabolism and heightened reactive oxygen species (ROS) attributes [5,6,7,8]. Thus, specific cancer cells are more vulnerable to ferroptosis. Moreover, various tumor suppressors, such as p53 and BRCA1-associated protein 1 (BAP1), have been discovered to deter cancer progression by obstructing ferroptosis [9]. Therefore, targeting ferroptosis may provide new therapeutic opportunities to treat cancers refractory to conventional therapies. On the other hand, ferroptosis, a newly discovered form of cell death, may contribute to inflammation and activate intrinsic immunity [10]. Studies have shown that ferroptosis is linked to elevated prostaglandin-endoperoxide synthase 2 (PTGS2) expression and prostaglandin E2 (PGE2) secretion, which accelerates arachidonic acid metabolism, releasing inflammatory mediators and activating the inflammatory response [11]. Ferroptosis may also involve the inflammatory process by producing lipoxygenase (LOX) and cyclooxygenase (COX) products [12]. This review aims to link cancer and ferroptosis, determine the influence of molecular mechanisms associated with the ferroptosis pathway on the occurrence and development of inflammation and cancer, and provide new ideas and effective targets for the prevention and treatment of cancer. Characteristics associated with ferroptosis Morphological features One study suggests that ferroptosis is morphologically and biochemically distinct from autophagy, apoptosis, and necrosis [1]. It differs from the morphological characteristics of typical necrosis and does not exhibit features such as rupture of the plasma membrane, cytoplasmic swelling, and moderate chromatin condensation. Unlike traditional apoptosis, apoptosis is characterized by plasma membrane blebbing, pseudopod retraction, reduction of cellular and nuclear volume, formation of apoptotic bodies and nuclear fragmentation, and chromatin condensation. Ferroptosis does not possess autophagic characteristics, for example, the accumulation of autophagic vacuoles (enclosed double-layer membrane structures). Ferroptosis is mainly characterized by small mitochondria, outer mitochondrial rupture, intact plasma membrane, normal nuclear size, and absence of chromatin condensation [13,14,15,16,17] (Table 1). Table 1 The features of ferroptosis, apoptosis, autophagy, Necroptosis, and Pyroptosis [13,14,15,16,17]. Full size table Biochemical features Biochemical features in ferroptosis involve iron accumulation, lipid peroxidation, generation of ROS, and depletion of glutathione peroxidase 4 (GPX4). Among these, the crucial factors are iron accumulation and lipid peroxidation [1, 13] (Table 1). Iron accumulation Iron is a metal with redox properties and is also one of the essential trace elements in the body. The abnormal distribution and content of iron in the body will impact normal physiological activities [3, 18]. The activation of ferroptosis, facilitated by agents such as Erastin and RSL3, occurs through the accumulation of iron within cells. This process not only directly generates excessive ROS by initiating the non-enzymatic Fenton reaction but also enhances the activity of lipoxygenase (ALOX) or EGLN prolyl hydroxylases (also known as PHD) [1, 19, 20]. Lipid peroxidation Lipid peroxidation is one of the key signals that initiate membrane oxidative damage during ferroptosis [1]. Lipid peroxidation can divide into non-enzymatic lipid peroxidation (auto-oxidation) and enzymatic lipid peroxidation, which is a reaction catalyzed by free radicals. ROS in auto-oxidation initiates the oxidation of polyunsaturated fatty acids (PUFAs), especially arachidonic acid peroxide and adrenalin, leading to the accumulation of peroxides. Enzymatic lipid peroxidation is regulated by LOX activity [3]. It can catalyze the production of a variety of lipid hydroperoxides from PUFAs. Fatty acids include saturated fatty acids (no double bonds), monounsaturated fatty acids (MUFAs, one double bond), and polyunsaturated fatty acids (PUFAs, >1 double bond) [21]. PUFAs (including linoleic acid and arachidonic acid) can stimulate RSL3-induced ferroptosis, while oleic acid, a monounsaturated fatty acid (MUFA), may protect cells from ferroptosis through neutralization [19]. Thus, it has an inhibitory effect on ferroptosis. Regulation of ferroptosis Iron metabolism Iron is one of the most important trace elements in the body. Normal physiological processes can be affected by abnormal distribution and content of iron in the body [18]. There are four main aspects to iron metabolism: absorption, storage, utilization, and excretion [22]. Iron ingested from food is absorbed by the epithelial cells of the duodenum, reduced to Fe2+ through iron reductase in the intestinal epithelial cells, and transported to the cells by divalent metal transporters [23]. Circulating Fe3+ enters cells via the TF/TFR-1 transport system and is reduced to Fe2+ by the metal reductase STEAP3. The reduced Fe2+ is transferred to the cytoplasm via DMT1 and is involved in a variety of subsequent physiological and biochemical processes, including DNA biosynthesis, oxygen transport, and regulation of metabolic pathways [24]. Fe2+ in the cytoplasm initially forms various iron-binding complexes. When the iron-binding complexes reach saturation, the excess Fe2+ accumulates in an unstable iron pool. The Fe2+ in the liable iron pool participates in the Fenton reaction to generate ROS, mainly hydroxyl radicals. This leads to membrane lipid peroxidation and ultimately ferroptosis [25]. Heat shock protein beta-1 (HSPB1) inhibits TFR-1 expression and reduces intracellular iron concentration [26]. Ferritin consists of two subunits, FTL and FTH1. It is the primary protein that stores iron ions [24]. The Nuclear receptor coactivator 4 (NCOA4) is an important molecule that mediates ferroptosis, and silencing NCOA4 decreases the level of liable iron pools and inhibits ferroptosis [14, 27]. However, by enhancing ferritinophagy through inhibition of cytosolic glutamate oxaloacetate transaminase 1 (GOT1), the level of labile iron pools increases, ultimately leading to ferroptosis [28] (Fig. 1). Fig. 1: Mechanisms of ferroptosis. figure 1 The figure shows the primary metabolic pathways regulating ferroptosis: iron metabolism, lipid metabolism, and amino acid metabolism. ACSL4 acyl-CoA synthetase long-chain family member 4, DMT1 divalent metal transporter 1, GPX4 glutathione peroxidase 4, GSH glutathione, GSS glutathione synthetase, GCL glutamate-cysteine ligase, HSPB1 heat shock protein beta-1, IREB2 iron response element-binding protein 2, LOX lipoxygenase, LPCAT3 lysophosphatidylcholine acyltransferase 3, NCOA4 nuclear receptor coactivator 4, FTL ferritin light chain, FTH1 ferritin heavy chain 1, NRF2 nuclear factor E2-related factor 2, PUFA polyunsaturated fatty acid, PE phosphatidylethanolamine, ROS reactive oxygen species, RSL3 Ras-selective lethal 3, STEAP3 six-transmembrane epithelial antigen of prostate 3 metalloreductase, SLC7A11 solute carrier family 7 member 11, TF transferrin, TFR1 transferrin receptor 1, VDAC2/3 voltage-dependent anion channel 2/3. Full size image Lipid metabolism PUFAs are significant components of the phospholipid bilayer and are crucial in regulating cell membrane fluidity. Nonetheless, PUFAs (such as arachidonic acid and epinephrine) are vulnerable to the Fenton reaction, which produces excessive peroxides that impair the phospholipid bilayer structure, thereby compromising cell membrane function [29,30,31]. Acyl-CoA synthase long-chain member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) enzymes are required for the biosynthesis and remodeling of polyunsaturated fatty acids [31]. Phosphatidylethanolamine (PE) is a glycerophospholipid present in cellular membranes. In mitochondria, PE makes up 40% and in other organelles, membrane accounts for about 15%–25% [32, 33]. PUFAs react with coenzyme A to produce acyl-CoA through the catalytic action of ACSL4 [34,35,36,37]. Subsequently, LPCAT3 facilitates the conversion of acyl-CoA to membrane phosphatidylethanolamine through esterification, resulting in the production of PUFA-PE [36, 38, 39]. Finally, the oxidation of polyunsaturated fatty acids (PUFA-PE) by LOX results in cellular ferroptosis [37] (Fig. 1). Amino acid metabolism Glutathione (GSH) is a tripeptide consisting of glycine, cysteine, and glutamic acid-containing Y-amido-hexapeptide and sulfhydryl groups, which is an important antioxidant [40, 41]. GSH functions intracellularly as a vital substrate for GPX4 [42]. The cell membrane features a class of heterodimers known as System Xc-, which is comprised of Solute Carrier Family 7 Member 11 (SLC7A11) and Solute Carrier Family 3 Member 2 (SLC3A2) [43]. The System Xc- enables the transfer of extracellular cystine to intracellular glutamate in a 1:1 proportion, which is succeeded by the production of GSH from intracellular cystine, aided by the actions of glutamate-cysteine ligase (GCL) and glutathione (GSS) [42, 44]. Cystine uptake in the majority of mammalian cells is mediated by SLC7A11, which is then followed by a reduction reaction that depletes nicotinamide adenine dinucleotide phosphate (NADPH) to produce cysteine [41]. Cysteine is a member of the group of amino acids containing sulfur. Additionally, cysteine can be converted from methionine through the transsulfuration pathway [45]. GPX4 and System Xc- play crucial roles in the amino acid metabolism of ferroptosis. Furthermore, GPX4 coenzyme GSH works to convert phospholipid peroxides to phospholipids, thereby shielding cells from ferroptosis [45]. It has been demonstrated that ROS primarily stem from the electron transport chain (ETC) complex within mitochondria. Inhibition of the ETC results in diminished accumulation of oxides, thereby hindering ferroptosis [46]. ROS production can impact the regulatory function of ferroptosis. Additionally, the regulation of ferroptosis can be influenced by mitochondrial tricarboxylic acid (TCA), and the inhibition of the TCA cycle in mitochondria can block the voltage-dependent channel 2/3 (VDAC2/3) to safeguard cells from ferroptosis [47]. In conclusion, the regulation of ferroptosis is closely linked to amino acid metabolism (Fig. 1). Physiological functions of ferroptosis Ferroptosis was initially introduced in 2012 as a form of cell death reliant on iron. Current research has found a close link between ferroptosis and a range of physiological processes. Biological processes connected to ferroptosis were primarily advanced through exploring markers of ferroptosis [48]. In tumor suppression and immune functions, many anti-oncogenes have been discovered to exert fractional tumor-suppression function by inducing ferroptosis. For instance, the tumor-suppressor gene p53, which is involved in tumor development, inhibits the expression of SLC7A11 [9]. Moreover, MLL4 deletion results in a significant suppression of ferroptosis in cutaneous squamous cell carcinoma [49]. Likewise, the tumor suppressive effects of BAP1 and NFS1 rely on the regulation of ferroptosis [50]. PUFA (Polyunsaturated fatty acid)-rich diets increase the production of PUFA-containing phospholipids (PLs), which promote tumor ferroptosis [30]. CD8+ T cells facilitate tumor cell ferroptosis by releasing IFNγ and inhibiting the expression of SLC7A11 [51]. CD8+ T cells also release AA (arachidonic acid), promoting tumor cell ferroptosis [48]. High-cholesterol foods enhance the expression of CD36 on the surface of CD8+ T cells, leading to the uptake of PUFAs in CD8+ T cells [52]. Selenium supplementation has been found to promote antiviral immunity. Selenium-enriched diets improved the expression of the selenoprotein GPX4, which inhibited ferroptosis in CD4+ TFH cells, promoting memory B cells and persistent viral immunity [53]. Ferroptosis markers increased with age in the brain tissues of rats and mice. Similarly, with increasing age, iron gradually increased, and GSH gradually decreased in nematodes, ultimately leading to ferroptosis. Ferroptosis was identified in nucleated erythrocytes before enucleation and maturation, suggesting its role in both the normal erythropoiesis process and the aging of various organs [48]. Ferroptosis and inflammation Abnormal activation of ferroptosis in many organs is involved in the development of many tumors or pathological processes (Fig. 2). Fig. 2 figure 2 Ferroptosis has played important roles in multiple system diseases. Full size image Inflammation is a crucial and innate physiological activity in the body. While a moderate inflammatory response benefits the organism, an excessive response can result in harm. The body initiates inflammation in response to exposure to various damaging factors. Clinically, inflammation often presents with redness, heat, swelling, and dysfunction. Inflammation-inducing agents related to lipid peroxidation and AA metabolism manifest during ferroptosis. AA is a Polyunsaturated fatty acid primarily present as PLs in cell membranes. When cell membranes are exposed to various stimuli, vast amounts of AA are released from PLs by phospholipase A2 (PLA2) and phospholipase C (PLC) [54,55,56], which is then metabolized into biologically active inflammatory mediators like eicosanoids prostaglandin (PG), interleukin (IL), tumor necrosis factor (TNF), and leukotriene (LT). These mediators can contribute to the inflammatory cascade. AA metabolism is involved in at least three metabolic pathways, namely the COX pathway, the LOX pathway, and the cytochrome p45 (CYP450) pathway [57]. The COX and LOX pathways are the primary routes for metabolizing AA into inflammatory mediators and breaking it down into leukotrienes, prostaglandins, and some peroxides [58]. COX enzymes facilitate the conversion of AA into prostaglandins (PGs). Two isoforms of COX exist, namely COX1 and COX2. COX1 is a beneficial enzyme widely present in various cell types, while COX2 is an inducible enzyme encoded by the PTGS2 gene. COX2 plays a vital role in activating macrophages or other inflammatory cells [59]. COX2 expression is minimal in normal physiological conditions but abundant in inflammatory cells. This phenomenon can lead to the transformation of inflammatory regions into pre-tumor microenvironments [60, 61]. COXs convert arachidonic acid to prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2), which generate a variety of biologically active PGs, including PGE2, prostaglandin D2 (PGD2), and prostaglandin I2 (PGI2), through the action of various isoenzymes. PGH2 is highly unstable and has a half-life of approximately 30 seconds. In the presence of thromboxane synthetase, thromboxane A2 (TXA2) may also be produced [62, 63]. Increased expression and release of PTGS2 in the prostate is associated with ferroptosis, which promotes arachidonic acid metabolism and the release of inflammatory factors through the upregulation of PTGS2 [11]. LOX is not only involved in oxidative lipidation but is also an important signal for ferroptosis, which also converts AA to inflammatory mediators such as leukotrienes (LTs) and lipoxygenase (LXs) [64]. The CYP450 pathway has the ability to metabolize arachidonic acid into epoxyeicosatrienoic acid (EET) and hydroxyeicosatetraenoic acid (HETE) [65]. It is hypothesized that ferroptosis may be closely associated with arachidonic acid metabolism and the inflammatory response. However, the precise mechanism of action remains unclear. Ferroptosis and cancer BAP1-mediated regulation of ferroptosis The BAP1 gene, associated with the suppression of tumors, encodes a nuclear deubiquitinating (DUB) enzyme that forms the polycomb repressive deubiquitinase (PR-DUB) complex. This complex epigenetically regulates gene expression by decreasing histone 2 A ubiquitination (H2Aub) on chromatin in nucleosomes [66,67,68,69,70,71]. The tumor-suppressor activity of BAP1 is mediated, in part, by the repression of SLC7A11 expression through deubiquitinating of H2A on the SLC7A11 promote. SLC7A11 facilitates the cellular uptake of cystine, which is the primary precursor for glutathione (GSH) biosynthesis. GSH is a crucial molecule for cellular resistance to oxidative stress [72]. Inhibition of SLC7A11 by the erastin increases lipid peroxidation, leading to ferroptosis [73]. The study found that overexpression of WT BAP1 in UMRC6 cells hindered the cellular uptake of cystine, resulting in reduced GSH levels and increased erastin-induced lipid peroxidation [50]. BAP1 suppresses the expression of SLC7A11 to inhibit cystine uptake, leading to lipid peroxidation and ferroptosis. SLC7A11, the cystine transporter protein, was identified as a critical BAP1 target gene in human cancers. Moreover, BAP1 mutants associated with cancer were found to lose their ability to repress SLC7A11 and to promote ferroptosis. In vivo experiments indicate that restoring BAP1 expression in BAP1-deficient cells suppresses the growth of xenografted tumors. Human tumor-associated mutations in BAP1 do not inhibit the expression of SLC7A11 and do not suppress tumors via promoting ferroptosis [50]. P53-mediated regulation of ferroptosis As a crucial suppressor gene of tumors, p53 takes part in numerous biological processes, including cell cycle inhibition, aging, and apoptosis. Almost half of the human tumor tissues display mutations or inactivation of the p53 gene. In addition, p53 may have antitumor effects by regulating intracellular ferroptosis. Specifically, under oxidative stress, p53 can either promote or inhibit ferroptosis [74]. Its pro-death functions include inhibiting SLC7A11 expression and promoting SAT1 expression [75]. Additionally, acetylation modification of the P53 DNA-binding region can regulate SLC7A11 expression, thereby promoting ferroptosis in certain cancer cells [9]. Notably, the acetylation-deficient mutant P533KR inhibits SLC7A11 expression and increases cell sensitivity to ferroptosis [76]. However, the mutant p534KR did not down-regulate SLC7A11 expression [76]. Additionally, p53 regulates ferroptosis by targeting SAT1 (spermine/spermine n1-acetyltransferase 1) [77, 78]. Silencing SAT1 significantly abrogates p53-mediated ferroptosis, while upregulation of SAT1 expression sensitizes cells to ferroptosis upon hypoxic conditions. Mechanistically, SAT1 did not affect the expression or activity of SLC7A11 and GPX4. Furthermore, the P53-SAT1-ALOX15 pathway regulates ferroptosis [77]. Another important aim in regulating ferroptosis during glutamine metabolism is the targeting of Glutaminase 2 (GLS2), a crucial mitochondrial glutaminase that has recently been studied and recognized as a fresh transcriptional objective of p53 [79]. Expression in tumor cells is linked to mitochondrial oxidative stress and ATP synthesis regulated by p53. In HepG2, LN-2024, and HCT116 cells, the expression of GLS2 facilitates the generation of glutathione in tumor cells, thus enhancing cellular antioxidant function [80]. Therefore, GLS2 may be a negative regulatory protein for ferroptosis. On the other hand, the pro-survival functions of p53 in ferroptosis include inhibiting dipeptidyl-peptidase 4 (DPP4) activity and promoting the promotion of CDKN1A/p21 expression. Research has shown that p53 has a pro-survival function in ferroptosis inhibition by blocking DPP4 activity. Knockout, knockdown, or pharmacologically inhibiting p53 boosted the anticancer efficacy of type I ferroptosis inducers (erastin and sulfasalazine). However, it had no significant effect on tumor cell killing by type II ferroptosis inducers (RSL3 and FIN56). DPP4 inhibitors completely blocked erastin-induced ferroptosis in CRC cells. When p53 is absent, DPP4 triggers membrane-associated DPP4-mediated lipid peroxidation through binding to NOX1 (NADPH oxidase 1) and forming the NOX1-DPP4 complex, leading to ferroptosis in CRC cells [81]. NADPH oxidases (NOX) are a group of proteins that transfer electrons into the cell and reduce oxygen to superoxide anion. NOX1 facilitates ROS production via NADPH, contributing to erastin-induced ferroptosis [1]. CDKN1A can achieve anti-oxidative stress by inhibiting apoptosis. CDKN1A/p21 plays an important role in p53-mediated DNA damage-induced cell cycle arrest [82]. It has been reported that the regulation of CDKN1A by p53 delays ferroptosis occurrence in tumor cells when Cys (cysteine) is absent. The activation of CDKN1A/p21-mediated GSH metabolism by p53 can inhibit cellular ferroptosis (Fig. 3). Fig. 3: Signaling pathways regulating ferroptosis in cancer. figure 3 ALOX arachidonate-15- lipoxygenase, CDKN1A cyclin-dependent kinase inhibitor 1A, DPP4 dipeptidyl-peptidase-4, GLS2 glutaminase 2, GSH glutathione, GPX4 glutathione peroxidase 4, NOX1 NADPH oxidase 1, ROS reactive oxygen species, SAT1 spermidine/spermine N1-acetyltransferase 1, SLC7A11 solute carrier family 7 member 11, HO-1 heme oxygenase 1, FTH1 ferritin heavy chain 1, NRF2 nuclear factor erythroid 2-related factor 2 NRF2. Full size image NRF2-mediated regulation of ferroptosis NRF2, encoded by the NFE2L2 gene, is precisely regulated by the E3-ubiquitin ligase system [83,84,85]. It can specifically target and regulate a diverse range of proteins that are closely linked to the ferroptosis cascade. It should however be noted that NRF2 activation can potentially trigger tumor progression and resistance to therapy [86]. While NRF2 inducers are reported to have a protective effect on normal cells from carcinogens, NRF2 inhibitors are useful in reducing the resistance to ferroptosis in patients with tumors [87]. Some HNC cells were found to evade ferroptosis caused by inhibition of GPX4, and HNC cells insusceptible to RSL3 or ML162 were resistant to ferroptosis induced by GPX4 inhibitors. However, the resistance was reduced by inhibition of Keap1 or upregulation of the NRF2 gene [88]. Additionally, the research discovered that the expression of NRF2 was considerably enhanced in HNC cells following the usage of artesunate. Furthermore, the deletion of NRF2 resulted in decreased resistance to ferroptosis caused by artesunate due to GSH deficiency and heightened ROS levels both in vivo and in vitro [89]. It has been reported that NRF2 is significantly expressed in various malignancies and is closely linked to the malignant phenotype and patient prognosis [90]. Additionally, it has been uncovered that NRF2 improves the chemosensitivity of tumor cells to sorafenib-induced ferroptosis [90]. Sun et al. [91] demonstrated that quiescin sulfhydryl oxidase 1 (QSOX1) inhibited NRF2 activation during sorafenib-induced ferroptosis in HCC cells. A different research team also indicated that erastin, sorafenib, and buthionine sulfonimine, which are ferroptosis inducers, augmented NRF2 expression in HCC cells [92]. Conversely, the downregulation of NRF2 by FTH (ferritin heavy chain), NQO1 (NAD(P)H quinone oxidoreductase-1), and HO-1 (heme oxygenase1) amplified the sensitivity to ferroptosis in HCC [92]. Additionally, Glutathione S-transferase zeta 1 (GSTZ1) [93] and Sigma-1 receptor (SIR) [94] improved the sensitivity of HCC cells to sorafenib-induced ferroptosis by down-regulating NRF2. High NRF2 expression stimulated GBM cell proliferation and facilitated the oncogenic transformation. Furthermore, the activation of NRF2 was observed to confer resistance to erastin- and RSL3-induced ferroptosis in GBM cells [95] (Fig. 3). EMT-mediated regulation of ferroptosis Epithelial-mesenchymal transition (EMT) refers to the process whereby epithelial cells lose their polarity and intercellular adhesion while acquiring mesenchymal properties associated with invasive and migratory capabilities [96]. Research has demonstrated that transcription factors, including SNAI1, TWIST1, and ZEB1, can advance EMT and promote drug resistance in tumor cells [97]. These findings might be potential therapeutic targets in oncology. Furthermore, EMT signaling promotes ferroptosis. 2,2’-Di-pyridylketone hydrazone dithiocarbamate s-butyric acid (DpdtbA), an iron chelator, exhibited potent antitumor effects in gastric and esophageal cancer cells. DpdtbA can also inhibit EMT by activating the P53 and PHD2/HIF1α pathways [98]. Furthermore, the use of an iron chelator reduced cigarette smoke exposure (CSE)-induced EMT mitochondrial malfunction and cell death in lung epithelial cells. Iron chelators were identified as inhibitors of cell death induction after RSL3 treatment [99]. In addition, The expression of Bach1 was increased in glioma cells and was strongly associated with EMT. Notably, the development of ferroptosis is inhibited by overexpression of Bach1 in glioma cells [100]. The TGFβ family comprises three TGFβs, two activins, numerous bone morphogenetic protein (BMP) homologs, and various homodimers and heterodimers of ligands. Intracellular lipid peroxidation is induced by TGF-β1, which promotes EMT in melanoma cells and consequently strengthens cellular ferroptosis [101]. In addition, e-cadherin-mediated cell-to-cell contact activates the Hippo pathway, ultimately reducing a process known as ferroptosis. This, in turn, inhibits the activity of YAP, a protein that co-regulates transcription associated with ferroptosis. YAP is activated after the initiation of EMT, therefore increasing cells’ vulnerability to ferroptosis [102]. It has also been found that incorporating histone deacetylase (HDAC) inhibitors can promote EMT in SW13 cells, further increasing their sensitivity to ferroptosis [103]. HIF-mediated regulation of ferroptosis Hypoxia is a crucial factor in promoting tumor growth and treatment resistance [104]. HIF (Hypoxia‑inducible factor), an essential regulator of hypoxia, is made up of an oxygen-unstable subunit, including HIF1α, EPAS1 (HIF2α), and HIF3α, and an expression-regulated subunit, ARNT [105]. Under normal oxygen levels, HIF1α and HIF2α are hydroxylated by members of the EGLN family. Subsequently, HIF1α and HIF2α bind to E3 ubiquitination ligase, VHL, and are eventually degraded through the proteasome pathway. Under hypoxia conditions, the inactivation of hydroxylase results in the intracellular accumulation of HIF-1α, HIF2α, and ARNT to form heterodimers, which regulate cellular adaptation to hypoxia and survival. HIF-1α and HIF-2α are aberrantly expressed in tumors and intimately linked to patient prognosis [106]. In renal clear cell carcinoma, HIF is a key driver of ferroptosis. Further, the inclusion of HIF while inhibiting GPX4 mitigates GPX4-mediated ferroptosis. HIF-1α and HIF-2α have been identified as regulators of ferroptosis in renal clear cell carcinoma cells [107]. Inducing the expression of HIF-1α through increasing the expression of fatty acid-binding proteins 3 and 7 under hypoxic conditions inhibits ferroptosis [108]. Solute carrier family 1 member 1 (SLC1A1) was found to be a membrane glutamate transporter that functions to transport extracellular glutamate into the cell, driving SLC7A11-mediated cystine uptake [109]. Similarly, in gastric cancer cells, HIF-1α inhibits ferroptosis by up-regulating the level of SLC7A11 [107]. By contrast, HIF-2α activated in RCC-derived cells enhanced polyunsaturated lipids and caused lipid peroxidation through hypoxia-inducible, lipid droplet-associated protein (HILPDA) activation [8]. Moreover, scholarly articles report that HIF-2α activation in colorectal cancer notably increases gene expression relating to lipid and iron metabolism, promoting the cell prone to ferroptosis [8]. Targeting ferroptosis in cancer treatment Tumor resistance to chemical drugs poses a significant challenge to oncology treatment. Ferroptosis, a distinct form of cell death, plays a crucial role in inhibiting tumor growth and has opened new avenues for treating chemotherapy-resistant tumors. A mounting body of research has highlighted ferroptosis as a possible target for overcoming chemotherapy resistance [6, 7, 110]. Therefore, ferroptosis inducers have a pivotal role in treating tumor resistance. Ferroptosis and acquired drug resistance in cancers Inducing “ferroptosis” is a viable method of combating drug-resistant tumor cells. Recent research has demonstrated that YAP/TAZ potentially facilitates the resistance of hepatocellular carcinoma cells to sorafenib-induced ferroptosis through the co-regulation of SLC7A11 expression with ATF4. Thus, YAP/TAZ could constitute a crucial molecular mechanism regulating ferroptosis in hepatocellular carcinoma cells while also promoting the emergence of sorafenib resistance [111]. One of the key molecular mechanisms that regulate ferroptosis in hepatocellular carcinoma cells and promote sorafenib resistance. In particular, NRF2 exhibits the capacity to regulate the expression of multiple target genes, including GPX4 and SLC7A11, within the SLC7A11-GPX4-GSH pathway. Consequently, this can influence the susceptibility of tumor cells to drug treatment [86, 112, 113]. Furthermore, ZEB1 expression was significantly upregulated in stromal cells resistant to chemotherapy but appeared to be more susceptible to ferroptosis induced by statin treatment or GPX4 inhibition [7]. Additionally, ferroptosis was found to be effective in treating drug-resistant neuroblastomas. Ferritin A-induced ferroptosis effectively eradicated high-risk neuroblastoma cells and inhibited their growth [114]. Ferroptosis inducers for cancer therapy Targeting system Xc- System Xc- inhibitors can impact the uptake of Cys in cells, thereby affecting protein folding regulation. The incomplete protein folding accumulates and creates cellular stress, which ultimately leads to cellular ferroptosis. By inhibiting System Xc- directly, erastin can reduce GSH levels [115]. In RAS-bearing tumor cells, RAF/MEK/ERK is a vital pathway for erastin-induced ferroptosis. The mitochondrial voltage-dependent anion channel (VDAC) is a targeted molecule of erastin. Knockdown of VDAC2/3 leads to resistance to erastin. Erastin induces ferroptosis in tumor cells and enhances the therapeutic ability of conventional antitumor drugs such as doxorubicin and cisplatin [116, 117]. However, erastin is challenging to dissolve in water and metabolically unstable in vivo. Piperazine erastin (PE) has superior water solubility and stability compared to erastin [11]. Furthermore, significant enhancements have been made to the water solubility and anticancer performance of Ketone erastin [118]. Sulfasalazine (SAS) is a prevalent anti-inflammatory drug in clinical practice. The FDA categorizes SAS as a primary medication for treating rheumatoid arthritis [119]. Additionally, it has been discovered that SAS triggers intracellular ferroptosis by hindering System Xc-. However, SAS is significantly less potent than erastin. Studies have shown that SAS can induce ferroptosis in various types of tumor cells, including HT-1080, Calu-1, and 143 B. Additionally, it is beneficial as a combination therapy in improving the outcome of gliomas [115]. Sorafenib is a multikinase inhibitor that demonstrates effective treatment in advanced cancers such as renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer [115]. Although, there is evidence that some tumor cells have developed resistance to sorafenib treatment. Sorafenib has the capability to inhibit ferroptosis in HCC through the activation of NRF2 and Rb, among others [120]. The high affinity of the NRF2 transcription factor MT-1G in cells is associated with this phenomenon [121]. Blocking the activation of the MT-1G signaling pathway using sorafenib may decrease resistance to sorafenib treatment and increase efficacy [122]. Ferroptosis can be triggered in some tumor cells via blockade of System Xc- mediated cystine uptake, but transcriptional activation of the transsulfuration pathway in other tumor cells allows them to convert from methionine to cysteine. Consequently, System Xc- inhibitors cannot induce cellular ferroptosis in these cells [123]. Induced degradation of GPX4 In addition, the induction of ferroptosis can be achieved through the regulation of GPX4 levels, a key regulatory protein for ferroptosis, which has a crucial protective role against the process in organisms. GPX4 utilizes GSH as a substrate to reduce ROS to the corresponding fatty alcohols and prevent ROS accumulation [124]. GSH, an antioxidant, has been long recognized as a weak spot of cancer [125, 126]. Direct GPX4 activity targeting has the potential to trigger ferroptosis in cells [27]. Studies have revealed that antitumor medications heavily rely on GPX4. In vitro, administration of GPX4 inhibitors eliminates cancer cells and hinders their reappearance in vivo. The molecule RSL3 directly curbs GPX4 expression, impeding ferroptosis [6, 127]. RSL3 interacts with enzymes involving nucleophilic interactions, such as cysteine, serine, and selenocysteine, and modifies GPX4, rendering the enzyme inactive [123]. FIN56, a ferroptosis inducer derived from CIL56, demonstrates greater selectivity for ferroptosis in comparison to its parent compound. It catalyzes GPX4 degradation through ACC mediation. In addition, FIN56 induced coenzyme Q10 (CoQ10) depletion through interaction with squalene synthase (SQS), thereby increasing the sensitivity of cells to ferroptosis [128]. Furthermore, withaferin A promotes neuroblastoma (NB) cell death by increasing LIP levels through Hmox1, in addition to inactivating GPX4 [114]. BAY 87-2243, a known inhibitor of IκBa, upregulates Hmox1 in a nuclear factor manner independent of kb, thus promoting iron accumulation and inducing ferroptosis in tumor cells [129]. Additionally, FINO2, an endogenous peroxidase 1, 2-dioxygenase, induces ferroptosis in tumor cells by oxidizing iron and inactivating GPX4 [130]. Nanoparticle inducers In recent years, Nano ferroptosis inducers have attracted great attention for cancer therapy [131, 132]. Nanoscale ferroptosis inducers can be loaded onto nanocarriers to enhance solubility and biocompatibility [118]. Furthermore, nanomaterials have the potential to disturb the metabolic balance of an organism by interfering with intracellular biochemical processes, which can result in intracellular ferroptosis [123]. The initial discovery of a nanoparticle ferroptosis inducer, αMSH-PEG-C’ dots, was documented in 2016 [133]. As observed in cancer cells, injecting this inducer caused an escalation in intracellular iron levels, accompanied by ROS production and GSH depletion, ultimately triggering ferroptosis [134]. An alternative method involves manufacturing iron-containing nanoparticles capable of delivering and releasing iron to cancerous cells [135, 136]. Liu et al. devised a technique that engrosses Fe3+ and tannic acid (TA) onto the surface of SRF, resulting in SRF@FeIIIITA (SFT). Furthermore, SFT experiences damage to its nuclear-corona nanostructure when subjected to a lysosomal micro-acidic environment, eliciting ferroptosis via the inhibitory properties of SRF on GPX4. Additionally, tannic acid exhibits a potent acidic reducing ability, reducing Fe3+ to Fe2+ and generating reactive oxygen species, thereby promoting ferroptosis [137]. Shen et al. attempted to increase the concentration of each reactant (Fe3+, Fe2+, H2O2) under different conditions in the system to accelerate ROS generation [138]. Aside from regulating the metabolism of iron and reactive oxygen species, nanomaterials can also trigger iron-dependent cell death by controlling GSH levels [139]. In addition to the aforementioned, Wang et al. have produced an inducer of iron death using arginine-rich manganese silicate nanobubbles, specifically arginine-capped manganese silicate nanobubbles (AMSNs), which possess a notable ability to scavenge GSH [140]. In conclusion, the use of ferroptosis inducers is of paramount importance in tumor therapy. Conclusions Ferroptosis is a newly discovered type of cell demise literature that plays a significant role in numerous diseases. 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Author information Authors and Affiliations School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China Xin Jin, Jiuren Tang, Xiangyu Qiu, Xiaoya Nie, Shengming Ou, Rongxin Zhang & Jinrong Zhu Biomedicine Research Centre, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China Geyan Wu State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China Geyan Wu Contributions All authors listed have made a direct, substantial, and intellectual contribution to the work and approved the submitted version for publication. Corresponding authors Correspondence to Geyan Wu, Rongxin Zhang or Jinrong Zhu. 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Cell Death Discov. 10, 45 (2024). https://doi.org/10.1038/s41420-024-01825-7 Download citation Received 20 November 2023 Revised 11 January 2024 Accepted 16 January 2024 Published 24 January 2024 DOI https://doi.org/10.1038/s41420-024-01825-7 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Subjects Cancer Cancer therapy This article is cited by Prognostic and immunological implications of heterogeneous cell death patterns in prostate cancer Ming WangBangshun DaiXiansheng Zhang Cancer Cell International (2024) FUT2 promotes colorectal cancer metastasis by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1 Chenfei DongYue ZhangXiaoming Chen Communications Biology (2024) An Overview of Hexavalent Chromium-Induced Necroptosis, Pyroptosis, and Ferroptosis Saulesh KurmangaliyevaKristina BaktikulovaKairat Kurmangaliyev Biological Trace Element Research (2024) Download PDF Sections Figures References Abstract Facts Open questions Introduction Characteristics associated with ferroptosis Regulation of ferroptosis Physiological functions of ferroptosis Ferroptosis and inflammation Ferroptosis and cancer Targeting ferroptosis in cancer treatment Ferroptosis and acquired drug resistance in cancers Ferroptosis inducers for cancer therapy Conclusions References Funding Author information Ethics declarations Additional information Rights and permissions About this article This article is cited by Advertisement Cell Death Discovery (Cell Death Discov.) 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• 医療用医薬品 : テリボン List Top 添付文書情報 商品詳細情報 医薬品情報 総称名 テリボン 一般名 テリパラチド酢酸塩 欧文一般名 Teriparatide Acetate 製剤名 テリパラチド酢酸塩注射液 薬効分類名 骨粗鬆症治療剤 薬効分類番号 2439 ATCコード H05AA02 KEGG DRUG D03358 テリパラチド酢酸塩 商品一覧 相互作用情報 KEGG DGROUP DG00512 テリパラチド 商品一覧 DG03232 骨粗鬆症治療薬 商品一覧 JAPIC 添付文書(PDF) この情報は KEGG データベースにより提供されています。 日米の医薬品添付文書はこちらから検索することができます。 添付文書情報2022年10月 改訂（第2版） 2.禁忌 4.効能または効果 6.用法及び用量 8.重要な基本的注意 10.相互作用 11.副作用 16.薬物動態 17.臨床成績 18.薬効薬理 商品情報 3.組成・性状 販売名 欧文商標名 製造会社 YJコード 薬価 規制区分 テリボン皮下注28.2μgオートインジェクター Teribone Injection 旭化成ファーマ 2439401G1024 5995円／キット 処方箋医薬品注） 2. 禁忌 次の患者には投与しないこと 2.1　次に掲げる骨肉腫発生のリスクが高いと考えられる患者［15.2参照］ ・骨ページェット病 ・原因不明のアルカリフォスファターゼ高値を示す患者 ・小児等及び若年者で骨端線が閉じていない患者［9.7参照］ ・過去に骨への影響が考えられる放射線治療を受けた患者 2.2　高カルシウム血症の患者［8.3、10.2参照］ 2.3　原発性の悪性骨腫瘍もしくは転移性骨腫瘍のある患者［症状を悪化させるおそれがある］ 2.4　骨粗鬆症以外の代謝性骨疾患の患者（副甲状腺機能亢進症等）［症状を悪化させるおそれがある］ 2.5　本剤の成分又はテリパラチド（遺伝子組換え）に対し過敏症の既往歴のある患者 2.6　妊婦又は妊娠している可能性のある女性［9.5参照］ 4. 効能または効果 骨折の危険性の高い骨粗鬆症 5. 効能または効果に関連する注意 本剤の適用にあたっては、低骨密度、既存骨折、加齢、大腿骨頸部骨折の家族歴等の骨折の危険因子を有する患者を対象とすること。 6. 用法及び用量 通常、成人には、テリパラチドとして28.2μgを1日1回、週に2回皮下注射する。 なお、本剤の投与は24ヵ月間までとすること。 7. 用法及び用量に関連する注意 7.1　投与間隔は原則3〜4日間隔とすること。 7.2　本剤を投与期間の上限を超えて投与したときの安全性及び有効性は確立していないので、本剤の適用にあたっては、投与期間の上限を守ること。［15.2、17.1.1-17.1.3参照］ 7.3　本剤の投与をやむを得ず一時中断したのちに再投与する場合であっても、投与の合計が24ヵ月（208回）を超えないこと。また、24ヵ月（208回）の投与終了後、再度24ヵ月（208回）の投与を繰り返さないこと。 7.4　テリパラチド（遺伝子組換え）製剤から本剤に切り替えた経験はなく、その安全性は確立していない。なお、テリパラチド（遺伝子組換え）製剤から本剤に切り替えたときにおける本剤の投与期間の上限は検討されていない。［15.2参照］ 7.5　アバロパラチド製剤から本剤に切り替えた経験はなく、その安全性は確立していない。 8. 重要な基本的注意 8.1　本剤投与直後から数時間後にかけて、ショック、一過性の急激な血圧低下に伴う意識消失、痙攣、転倒があらわれることがある。投与開始後数ヵ月以上を経て初めて発現することもあるので、本剤投与時には以下の点に留意するよう患者に指導すること。［11.1.2参照］ ・投与後30分程度はできる限り安静にすること。 ・投与後に血圧低下、めまい、立ちくらみ、動悸、気分不良、悪心、顔面蒼白、冷汗等が生じた場合には、症状がおさまるまで座るか横になること。 8.2　一過性の血圧低下に基づくめまいや立ちくらみ、意識消失等があらわれることがあるので、高所での作業、自動車の運転等危険を伴う作業に従事する場合には注意させること。 8.3　本剤の薬理作用により、投与約4から6時間後を最大として一過性の血清カルシウム値上昇がみられる。本剤投与中に血清カルシウム値上昇が疑われる症状（便秘、悪心、嘔吐、腹痛、食欲減退等）が本剤投与翌日以降も継続して認められた場合には、速やかに診察を受けるよう患者に指導すること。また、血清カルシウム値の測定を行い、持続性高カルシウム血症と判断された場合には、本剤の投与を中止すること。［2.2、10.2参照］ 8.4　本剤の自己注射にあたっては、患者に十分な教育訓練を実施したのち、患者自ら確実に投与できることを確認した上で、医師の管理指導のもとで実施すること。また、器具の安全な廃棄方法について指導を徹底すること。本剤の使用説明書を必ず読むよう指導すること。 9. 特定の背景を有する患者に関する注意 9.1　合併症・既往歴等のある患者 9.1.1　低血圧の患者 一過性の血圧低下があらわれることがある。 9.1.2　心疾患のある患者 患者の状態を観察し、病態の悪化がないか注意しながら本剤を投与すること。副甲状腺ホルモンは血管平滑筋の弛緩作用や心筋への陽性変時・陽性変力作用を示すことが報告されている。なお、重篤な心疾患のある患者は臨床試験では除外されている。 9.1.3　尿路結石のある患者及びその既往歴のある患者 症状を悪化させるおそれがある。 9.1.4　閉経前の骨粗鬆症患者 閉経前の骨粗鬆症患者を対象とした有効性及び安全性を指標とした臨床試験は実施していない。 9.2　腎機能障害患者 定期的に腎機能検査を行うこと。 9.2.1　重度の腎機能障害患者 臨床薬理試験において、血中からのテリパラチドの消失に遅延が認められている。［16.6.1参照］ 9.3　肝機能障害患者 9.3.1　重篤な肝機能障害を有する患者 臨床試験では重篤な肝機能障害を有する患者は除外されている。 9.4　生殖能を有する者 妊娠する可能性のある女性には、治療上の有益性が危険性を上回ると判断される場合にのみ投与すること。また、本剤投与期間中は有効な避妊を行うように指導すること。妊娠が認められた場合には、本剤の投与を中止すること。［9.5参照］ 9.5　妊婦 妊婦又は妊娠している可能性のある女性には、投与しないこと。ウサギを用いた静脈内投与による器官形成期投与試験において、胎児毒性（胎児死亡）が認められている。［2.6、9.4参照］ 9.6　授乳婦 治療上の有益性及び母乳栄養の有益性を考慮し、授乳の継続又は中止を検討すること。 9.7　小児等 小児等及び若年者で骨端線が閉じていない患者には投与しないこと。これらの患者を対象とした臨床試験は実施していない。これらの患者では、一般に骨肉腫発現のリスクが高いと考えられている。［2.1参照］ 9.8　高齢者 患者の状態を観察し、十分に注意しながら本剤を投与すること。一般に高齢者では生理機能が低下していることが多い。 10. 相互作用 10.2　併用注意 ジギタリス製剤 ジゴキシン等 ［2.2、8.3参照］ 高カルシウム血症に伴う不整脈があらわれることがある。 血清カルシウム値が上昇すると、ジギタリス剤の作用が増強される。 活性型ビタミンD製剤 アルファカルシドール カルシトリオール エルデカルシトール マキサカルシトール ファレカルシトリオール等 血清カルシウム値が上昇するおそれがあるため、併用は避けることが望ましい。 相加作用 11. 副作用 11.1　重大な副作用 次の副作用があらわれることがあるので、観察を十分に行い、異常が認められた場合には投与を中止するなど適切な処置を行うこと。 11.1.1　アナフィラキシー（頻度不明） 11.1.2　ショック（頻度不明）、意識消失（頻度不明） ショック、一過性の急激な血圧低下に伴う意識消失があらわれることがあり、心停止、呼吸停止を来した症例も報告されている。異常が認められた場合には、適切な処置を行い、次回以降の投与中止を考慮すること。［8.1参照］ 11.2　その他の副作用 次の副作用があらわれることがあるので、観察を十分に行い、異常が認められた場合には投与を中止するなど適切な処置を行うこと。 5％以上 0.1〜5％未満 頻度不明 消化器 悪心、嘔吐 腹部不快感、消化不良、食欲減退、便秘、下痢、腹痛、逆流性食道炎、口腔内不快感、口渇、虚血性大腸炎、口唇腫脹 胃炎、胃潰瘍、腹部膨満、流涎過多、裂孔ヘルニア、おくび、味覚異常、口内乾燥、心窩部不快感、口角口唇炎、口内炎 精神神経系 頭痛 めまい、傾眠、頭部不快感、感覚鈍麻（四肢、顔、口のしびれ感等） 不眠症、振戦、鎮静、感情不安定、注意力低下、記憶障害、耳鳴、灼熱感、痙攣 眼 眼瞼浮腫 眼瞼下垂、視力障害、結膜充血、眼痛、霧視 腎臓 血中クレアチニン増加、尿中血陽性、頻尿 BUN上昇、腎機能障害、尿中蛋白陽性、慢性腎炎 循環器 血圧低下、血圧上昇、動悸、徐脈、不整脈 起立性低血圧、上室性頻脈、心室性期外収縮、心電図異常、狭心痛、潮紅、蒼白、洞結節機能不全、心房細動 過敏症 紅斑 発疹、蕁麻疹、そう痒症、アレルギー性結膜炎、アレルギー性鼻炎 肝臓 肝機能障害、ALP上昇、ALT上昇、AST上昇、γ-GTP上昇 代謝異常 高尿酸血症、高カルシウム血症 CK上昇、血中リン減少、ALP低下、アルブミン・グロブリン比減少、血中カリウム減少、血中カリウム増加、血中カルシウム増加、血中クロール減少、血中クロール増加、血中コレステロール増加、血中ナトリウム減少、血中ブドウ糖増加、脱水 血液 貧血 好酸球増加、好中球減少、リンパ球増加、血小板減少、好塩基球増加、好酸球減少、好中球増加、赤血球減少、単球減少、白血球減少、白血球増加、ヘマトクリット減少、ヘモグロビン減少、リンパ球減少 呼吸器 息詰まり感、咳嗽、喘息、鼻漏、副鼻腔炎、咽頭不快感 筋骨格 関節痛 筋骨格硬直、肩の石灰化腱炎、背部痛、四肢痛、四肢不快感、筋緊張、筋力低下、頚部痛、筋肉痛、骨痛、筋痙縮 投与部位 注射部位出血 注射部位疼痛、注射部位紅斑、注射部位血腫、注射部位反応 注射部位腫脹、注射部位不快感 その他 倦怠感 異常感（全身違和感、気分不良等）、発熱、悪寒、あくび、脱力感 胸部不快感、胸痛、多汗症、浮腫、熱感、甲状腺腫、自己免疫性甲状腺炎、リンパ節炎、末梢冷感、インフルエンザ様疾患、胆石症、皮下結節、皮下出血、尿中ウロビリン陽性、尿中ビリルビン増加、脱毛、疼痛、冷感、体重減少 13. 過量投与 13.1　症状 血圧低下、脈拍数増加、血清カルシウム値上昇が発現する可能性がある。 13.2　処置 本剤の投与を中止し、血圧、脈拍、血清カルシウム値の測定を行い、適切な措置を行うこと。 14. 適用上の注意 14.1　薬剤投与前の注意 14.1.1　室温に戻しておくこと。 14.1.2　投与直前まで本剤の先端部のキャップを外さないこと。キャップを外したら直ちに投与すること。 14.1.3　投与前に、内容物を目視により確認すること。なお、異物又は変色が認められる場合は使用しないこと。 14.2　薬剤投与時の注意 14.2.1　本剤は皮下注射のみに使用し、注射部位を腹部、大腿部又は上腕部として、広範に順序よく移動して注射すること。 14.2.2　本剤は、1回使用の製剤であり、再使用しないこと。 15. その他の注意 15.2　非臨床試験に基づく情報 雌雄ラットに本薬を皮下投与したがん原性試験において、投与量及び投与期間に依存して骨肉腫を含む骨腫瘍性病変の発生頻度が増加した。なお、ラットに無発がん量（4.5μg/kg/日）を投与した際の1週間当たりの曝露量（AUC）は、ヒトに臨床推奨用量（1週間当たり56.5μg）を投与した際の曝露量（AUC）の3.9〜11.6倍に相当する1)。［2.1、7.2、7.4参照］ 16. 薬物動態 16.1　血中濃度 16.1.1　単回投与 健康閉経後女性に本剤28.2μgを単回皮下投与したとき、腹部、大腿部、上腕部のいずれの投与部位でも血漿中テリパラチド酢酸塩濃度は速やかにピークに達し、また消失も速やかであった（表及び図参照）2)。 表　健康閉経後女性に本剤を皮下投与したときの薬物動態パラメータ Cmax（pg/mL） Tmax（min） T1/2（min） AUCinf（ng・min/mL） 腹部（n＝12） 267.1±74.5 25.8±14.7 45.5±7.6 28.8±6.8 大腿部（n＝12） 208.4±58.2 40.0±17.3 57.3±15.6※ 28.2±7.3※ 上腕部（n＝12） 286.3±74.8 35.0±9.8 50.8±20.0 31.74±7.4 ※n＝11 （Mean±SD） 図　健康閉経後女性に本剤を皮下投与したときの血漿中テリパラチド酢酸塩濃度の推移 16.1.2　反復投与 健康閉経後女性にテリパラチドとして28.2μgを週2回6週間反復皮下投与したとき、投与間隔に関わらず、反復投与によってCmax及びAUCinfは変化しなかった3)。 16.2　吸収 16.2.1　生物学的利用率 30代健康成人男性5例にテリパラチドとして14.1μgを静脈内投与注）したときのAUCinf4)及び健康閉経後女性11〜12例に本剤28.2μgを皮下投与したときのAUCinf2)の比から求めた絶対的生物学的利用率はほぼ100％であった。 また、健康閉経後女性11〜12例に本剤28.2μgを皮下投与したとき、腹部投与に対する相対的バイオアベイラビリティ（AUCinfの比、最小二乗平均値）は、上腕部で110％、大腿部で95.9％であった2)。 16.3　分布 16.3.1　分布容積 30代健康成人男性5例にテリパラチドとして14.1μgを静脈内投与注）したときの分布容積は307±78mL/kg、60代健康成人男性5例にテリパラチドとして14.1μgを静脈内投与注）したときの分布容積は426±190mL/kgであった4)。 16.3.2　血球移行性 健康成人5例の血液サンプルを用いて、テリパラチド酢酸塩の血球への移行性を評価した結果、血球移行性は37.0％であった5)（in vitro）。 16.3.3　組織分布 ラットでの検討より、皮下投与されたテリパラチド酢酸塩（125I標識体）は肝臓及び腎臓に分布することが示唆された6)。 16.4　代謝 ラット組織を用いた検討より、肝臓あるいは腎臓に分布したテリパラチド酢酸塩（125I標識体）は速やかに低分子の分解物へと代謝されることが示唆された6)。 16.5　排泄 健康閉経後女性16例にテリパラチドとして56.5μg注）を単回皮下投与したとき、24時間までに排泄された尿中にテリパラチド酢酸塩は検出されなかった7)。 16.6　特定の背景を有する患者 16.6.1　腎機能障害患者 腎機能障害者にテリパラチドとして56.5μg注）を単回皮下投与したときCmax及びAUCinfは腎機能の影響を大きく受けず、T1/2は高度腎障害者で延長したが（表参照）、本剤の投与間隔を考慮すれば血漿からの消失は十分に速やかであると考えられた（図参照）8)。したがって、腎機能の程度によって用法・用量を変更する必要はないと考えられた。なお、腎透析患者を対象とした試験は実施されていない。［9.2.1参照］ 表　テリパラチドを腎機能障害者に皮下投与したときの薬物動態パラメータ Cmax（pg/mL） Tmax（min） T1/2（min） AUCinf（ng・min/mL） 正常〜軽度（n＝8） （eGFR：62.3-88.5） 361.73±103.44 50.6±26.5 90.64±29.54 56.54±9.59 中等度（n＝5） （eGFR：35.0-58.5） 499.14±259.48 48.0±19.6 71.76±10.58 56.36±13.31 高度（n＝5） （eGFR：16.7-28.5） 424.68±268.40 54.0±25.1 297.99±240.38 63.36±22.99 eGFRの単位：mL/min/1.73m2 （Mean±SD） 図　腎機能障害者の血漿中テリパラチド酢酸塩濃度の経時推移 16.6.2　肝機能障害患者 (1)肝機能障害患者を対象とした試験は実施されていない。 (2)肝機能障害モデルラットにテリパラチドとして5.6μg/kgを単回皮下投与したときの薬物動態パラメータは、正常ラットの値とほぼ同様であった5)。 16.7　薬物相互作用 ヒト肝細胞を用いて検討した結果、テリパラチド酢酸塩はCYP1A2、2C9、2C19、2D6及び3A4を阻害せず9)、CYP1A2及び3A4を誘導しなかった10)（in vitro）。 注）本剤の承認された用法・用量は、「通常、成人には、テリパラチドとして28.2μgを1日1回、週に2回皮下注射する。なお、本剤の投与は24ヵ月間までとすること。」である。 17. 臨床成績 17.1　有効性及び安全性に関する試験 17.1.1　国内第III相試験（骨密度試験） 骨折の危険性の高い原発性骨粗鬆症患者を対象とした48週間投与の実薬対照二重盲検比較試験11)において、本剤（テリパラチドとして1回28.2μg）の週2回投与と対照薬（テリパラチドとして1回56.5μg）の週1回投与を比較した。その結果、最終観察時の腰椎（L2-L4）骨密度の平均変化率は本剤群（251例うち男性23例）が7.3％、56.5μg週1回投与群（239例うち男性22例）が5.9％であり、本剤の56.5μg週1回投与に対する非劣性が検証された（非劣性限界値：−1.6％）。［7.2参照］ 表　最終観察時及び各評価時点の腰椎（L2-L4）骨密度の平均変化率 観察週＼ 本剤 56.5μg週1回投与 差 95％信頼区間 n 平均変化率 n 平均変化率 24週後 245 5.0％ 233 3.8％ ＼ ＼ 48週後 231 7.5％ 224 6.0％ ＼ ＼ 最終観察時 251 7.3％ 239 5.9％ 1.3 0.400，2.283 本剤群の副作用発現頻度は39.7％（110／277例）であった。主な副作用は、本剤群では、悪心20.2％（56／277例）、倦怠感9.4％（26／277例）、嘔吐9.0％（25／277例）、頭痛5.8％（16／277例）、注射部位出血5.1％（14／277例）、56.5μg週1回投与群では、悪心31.9％（88／276例）、嘔吐13.0％（36／276例）、倦怠感12.0％（33／276例）、頭痛10.5％（29／276例）、発熱6.5％（18／276例）等であった。 17.1.2　テリパラチド56.5μg週1回投与製剤の国内第III相試験（72週投与の骨折及び骨密度試験） 骨折の危険性の高い原発性骨粗鬆症患者を対象にテリパラチドとして56.5μgを週1回又はプラセボを週1回72週間投与した第III相試験（二重盲検試験）のKaplan-Meier推定法に基づく新規椎体骨折発生率は下表のとおりであり（56.5μg週1回投与群261例うち男性13例、プラセボ群281例うち男性10例）、56.5μg週1回投与は新規椎体骨折の発生を有意に抑制した12)。72週後の相対リスク減少率は78.6％であり、新規椎体骨折発生率の群間差は11.4％であった。また、Cox回帰モデルに基づく相対リスク減少率は80％であった13)。 表　Kaplan-Meier推定法に基づく新規椎体骨折発生率 観察週＼ 56.5μg週1回投与（n＝261） プラセボ（n＝281） logrank検定 24週後 2.6％ 5.3％ p＜0.0001 48週後 3.1％ 10.4％ 72週後 3.1％ 14.5％ また、72週後の腰椎（L2-L4）骨密度の平均変化率は、56.5μg週1回投与群（107例うち男性6例）6.7％、プラセボ群（130例うち男性4例）0.3％であり、56.5μg週1回投与群はプラセボ群に対して有意な骨密度増加効果を示した（t検定、p＜0.0001）12)。［7.2参照］ 56.5μg週1回投与群の副作用発現頻度は43.8％（127／290例）であった。主な副作用は、悪心18.6％（54／290例）、嘔吐8.6％（25／290例）、頭痛7.6％（22／290例）、倦怠感6.2％（18／290例）、腹部不快感4.1％（12／290例）等であった12)。 17.1.3　テリパラチド56.5μg週1回投与製剤の国内第III相試験（24ヵ月投与の骨密度試験） 骨折の危険性の高い原発性骨粗鬆症患者を対象にテリパラチドとして56.5μgを週1回24ヵ月間投与した第III相試験（非盲検・非対照試験）において、腰椎（L2-L4）骨密度の平均変化率は72週後では8.4％（136例うち男性3例）、104週後（24ヵ月後）では9.9％（130例うち男性3例）であった14)。［7.2参照］ 副作用発現頻度は、58.2％（110／189例）であった。主な副作用は、悪心33.3％（63／189例）、嘔吐20.6％（39／189例）、頭痛16.4％（31／189例）、倦怠感16.4％（31／189例）、腹部不快感10.1％（19／189例）等であった。 18. 薬効薬理 18.1　作用機序 本薬はヒト副甲状腺ホルモンのN端側の1-34ペプチド断片である。本薬は前駆細胞の分化促進作用15)等により骨芽細胞の数を増加させ、骨形成を促進する16)。 18.2　骨強度、骨密度及び骨構造に及ぼす影響 卵巣摘除サルにテリパラチドとして1.1又は5.6μg/kgを週1回18ヵ月間反復投与した結果、対照と比較して腰椎及び大腿骨近位部の骨密度が増加した17)。卵巣摘除ラットにテリパラチドとして5.6又は28.2μg/kgを週3回12ヵ月間反復投与した結果、対照と比較して腰椎及び大腿骨近位部の骨密度が増加した18)。また、卵巣摘除ラットでは、テリパラチドとして5.6又は28.2μg/kgの投与により、腰椎及び大腿骨近位部の海綿骨の骨梁幅及び骨梁数が増加し、骨梁の連結性が改善すると共に、大腿骨骨幹部の皮質骨幅が増加し、腰椎及び大腿骨の骨強度が増加した18)。 18.3　骨代謝に及ぼす影響 卵巣摘除ラットにテリパラチドとして28.2μg/kgを週3回4週間反復投与した結果、腰椎において骨芽細胞面及び骨量が増加したが、破骨細胞面及び骨吸収面に変化は認められなかった16)。また、卵巣摘除ラットに卵巣摘除直後又は12ヵ月後からテリパラチドとして5.6μg/kgを週3回4ヵ月間反復投与した結果、骨形成マーカーである血清オステオカルシンが持続的に増加したが、骨吸収マーカーである尿中CTXは増加しなかった19)。 19. 有効成分に関する理化学的知見 19.1. テリパラチド酢酸塩 一般的名称 テリパラチド酢酸塩 一般的名称（欧名） Teriparatide Acetate 分子式 C181H291N55O51S2・5CH3COOH 分子量 4417.97 融点 210℃（分解） 物理化学的性状 白色の粉末で、においはないか又は、わずかに酢酸臭があり、味はない。 水又は酢酸（100）に極めて溶けやすい。 水溶液（1→1000）のpHは4.0〜6.0である。 吸湿性である。 KEGG DRUG D03358 20. 取扱い上の注意 本剤は冷蔵庫に入れ、凍結を避け、2〜8℃で遮光保存すること。 22. 包装 4オートインジェクター 23. 主要文献 Watanabe A.et al., J Toxicol.Sci., 37 (3), 617-629, (2012) 社内資料：113試験 Kumagai Y.et al., Clin Pharmacol Drug Dev., (2019), (（doi：10.1002/cpdd.687）) »PubMed »DOI 社内資料：健康成人男性での単回静脈内投与試験（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.7.1.2） 社内資料：薬物動態試験＜血球移行性（in vitro）＞（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.6.4.4） Serada M.et al., Xenobiotica, 42 (4), 398-407, (2012) 社内資料：健康高齢女性での臨床薬理試験（QT／QTc間隔に及ぼす影響の検討）（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.7.6.7） 社内資料：腎機能障害者での臨床薬理試験（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.6.4.5） 社内資料：薬物動態試験＜酵素阻害（in vitro）＞（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.6.4.5） 社内資料：薬物動態試験＜酵素誘導（in vitro）＞（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.7.2.2） Sugimoto T.et al., Osteoporos Int., 30 (11), 2321-2331 , (2019) 社内資料：骨折リスクの高い原発性骨粗鬆症に対するMN-10-Tの第III相骨折試験（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.7.6.10） Nakamura T.et al., J Clin Endocrinol Metab., 97 (9), 3097-3106, (2012) 社内資料：骨折の危険性の高い原発性骨粗鬆症に対するMN-10-Tの第III相骨量試験 Isogai Y.et al., J Bone Miner Res., 11 (10), 1384-1393, (1996) 社内資料：卵巣摘除ラットにおける骨形成促進作用（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.6.2.3） 社内資料：卵巣摘除カニクイザルを用いた18ヵ月間反復投与試験（テリボン皮下注用56.5μg：2011年9月26日承認、CTD2.6.2.3） Takao-Kawabata R.et al., Calcif Tissue Int., 97 (2), 156-168, (2015) Sugie-Oya A.et al., J Bone Miner Metab., 34 (3), 303-314, (2016) 24. 文献請求先及び問い合わせ先 文献請求先 旭化成ファーマ株式会社 くすり相談窓口 〒100-0006 東京都千代田区有楽町一丁目1番2号 電話：フリーダイヤル　0120-114-936（9：00〜17：45／土日祝、休業日を除く） 製品情報問い合わせ先 旭化成ファーマ株式会社 くすり相談窓口 〒100-0006 東京都千代田区有楽町一丁目1番2号 電話：フリーダイヤル　0120-114-936（9：00〜17：45／土日祝、休業日を除く） 26. 製造販売業者等 26.1　製造販売元 旭化成ファーマ株式会社 東京都千代田区有楽町一丁目1番2号 [ KEGG | KEGG DRUG | KEGG MEDICUS ] 2024/10/23 版