Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10155)

Regulator Name	Serine/threonine-protein kinase mTOR (MTOR)
Synonyms	FK506-binding protein 12-rapamycin complex-associated protein 1; FKBP12-rapamycin complex-associated protein; Mammalian target of rapamycin; Mechanistic target of rapamycin; Rapamycin and FKBP12 target 1; Rapamycin target protein 1 Click to Show/Hide
Gene Name	MTOR
Gene ID	2475
Regulator Type	Protein coding
Uniprot ID	P42345
Sequence	MLGTGPAAATTAATTSSNVSVLQQFASGLKSRNEETRAKAAKELQHYVTMELREMSQEES TRFYDQLNHHIFELVSSSDANERKGGILAIASLIGVEGGNATRIGRFANYLRNLLPSNDP VVMEMASKAIGRLAMAGDTFTAEYVEFEVKRALEWLGADRNEGRRHAAVLVLRELAISVP TFFFQQVQPFFDNIFVAVWDPKQAIREGAVAALRACLILTTQREPKEMQKPQWYRHTFEE AEKGFDETLAKEKGMNRDDRIHGALLILNELVRISSMEGERLREEMEEITQQQLVHDKYC KDLMGFGTKPRHITPFTSFQAVQPQQSNALVGLLGYSSHQGLMGFGTSPSPAKSTLVESR CCRDLMEEKFDQVCQWVLKCRNSKNSLIQMTILNLLPRLAAFRPSAFTDTQYLQDTMNHV LSCVKKEKERTAAFQALGLLSVAVRSEFKVYLPRVLDIIRAALPPKDFAHKRQKAMQVDA TVFTCISMLARAMGPGIQQDIKELLEPMLAVGLSPALTAVLYDLSRQIPQLKKDIQDGLL KMLSLVLMHKPLRHPGMPKGLAHQLASPGLTTLPEASDVGSITLALRTLGSFEFEGHSLT QFVRHCADHFLNSEHKEIRMEAARTCSRLLTPSIHLISGHAHVVSQTAVQVVADVLSKLL VVGITDPDPDIRYCVLASLDERFDAHLAQAENLQALFVALNDQVFEIRELAICTVGRLSS MNPAFVMPFLRKMLIQILTELEHSGIGRIKEQSARMLGHLVSNAPRLIRPYMEPILKALI LKLKDPDPDPNPGVINNVLATIGELAQVSGLEMRKWVDELFIIIMDMLQDSSLLAKRQVA LWTLGQLVASTGYVVEPYRKYPTLLEVLLNFLKTEQNQGTRREAIRVLGLLGALDPYKHK VNIGMIDQSRDASAVSLSESKSSQDSSDYSTSEMLVNMGNLPLDEFYPAVSMVALMRIFR DQSLSHHHTMVVQAITFIFKSLGLKCVQFLPQVMPTFLNVIRVCDGAIREFLFQQLGMLV SFVKSHIRPYMDEIVTLMREFWVMNTSIQSTIILLIEQIVVALGGEFKLYLPQLIPHMLR VFMHDNSPGRIVSIKLLAAIQLFGANLDDYLHLLLPPIVKLFDAPEAPLPSRKAALETVD RLTESLDFTDYASRIIHPIVRTLDQSPELRSTAMDTLSSLVFQLGKKYQIFIPMVNKVLV RHRINHQRYDVLICRIVKGYTLADEEEDPLIYQHRMLRSGQGDALASGPVETGPMKKLHV STINLQKAWGAARRVSKDDWLEWLRRLSLELLKDSSSPSLRSCWALAQAYNPMARDLFNA AFVSCWSELNEDQQDELIRSIELALTSQDIAEVTQTLLNLAEFMEHSDKGPLPLRDDNGI VLLGERAAKCRAYAKALHYKELEFQKGPTPAILESLISINNKLQQPEAAAGVLEYAMKHF GELEIQATWYEKLHEWEDALVAYDKKMDTNKDDPELMLGRMRCLEALGEWGQLHQQCCEK WTLVNDETQAKMARMAAAAAWGLGQWDSMEEYTCMIPRDTHDGAFYRAVLALHQDLFSLA QQCIDKARDLLDAELTAMAGESYSRAYGAMVSCHMLSELEEVIQYKLVPERREIIRQIWW ERLQGCQRIVEDWQKILMVRSLVVSPHEDMRTWLKYASLCGKSGRLALAHKTLVLLLGVD PSRQLDHPLPTVHPQVTYAYMKNMWKSARKIDAFQHMQHFVQTMQQQAQHAIATEDQQHK QELHKLMARCFLKLGEWQLNLQGINESTIPKVLQYYSAATEHDRSWYKAWHAWAVMNFEA VLHYKHQNQARDEKKKLRHASGANITNATTAATTAATATTTASTEGSNSESEAESTENSP TPSPLQKKVTEDLSKTLLMYTVPAVQGFFRSISLSRGNNLQDTLRVLTLWFDYGHWPDVN EALVEGVKAIQIDTWLQVIPQLIARIDTPRPLVGRLIHQLLTDIGRYHPQALIYPLTVAS KSTTTARHNAANKILKNMCEHSNTLVQQAMMVSEELIRVAILWHEMWHEGLEEASRLYFG ERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQA WDLYYHVFRRISKQLPQLTSLELQYVSPKLLMCRDLELAVPGTYDPNQPIIRIQSIAPSL QVITSKQRPRKLTLMGSNGHEFVFLLKGHEDLRQDERVMQLFGLVNTLLANDPTSLRKNL SIQRYAVIPLSTNSGLIGWVPHCDTLHALIRDYREKKKILLNIEHRIMLRMAPDYDHLTL MQKVEVFEHAVNNTAGDDLAKLLWLKSPSSEVWFDRRTNYTRSLAVMSMVGYILGLGDRH PSNLMLDRLSGKILHIDFGDCFEVAMTREKFPEKIPFRLTRMLTNAMEVTGLDGNYRITC HTVMEVLREHKDSVMAVLEAFVYDPLLNWRLMDTNTKGNKRSRTRTDSYSAGQSVEILDG VELGEPAHKKTGTTVPESIHSFIGDGLVKPEALNKKAIQIINRVRDKLTGRDFSHDDTLD VPTQVELLIKQATSHENLCQCYIGWCPFW Click to Show/Hide
Family	PI3/PI4-kinase family
Function	Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation. Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1- pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser- 758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions. Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms. Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks. Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex. Click to Show/Hide
HGNC ID	HGNC:3942
KEGG ID	hsa:2475

Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)

MTOR can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).

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Stearoyl-CoA desaturase (SCD) [Suppressor]

Target Info

In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[1]
Target for Ferroptosis	Suppressor
Responsed Disease	Pancreatic cancer		ICD-11: 2C10	Disease Info
Responsed Drug	Everolimus		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	BON-1 cells	Pancreatic serotonin-producing neuroendocrine tumor	Homo sapiens	CVCL_3985
In Vitro Model	QGP-1 cells	Pancreatic somatostatinoma	Homo sapiens	CVCL_3143
Response regulation	The negative correlation between MEN1 and SCD1 is further verified in clinical specimens. Furthermore, BON-1 and QGP-1 cells with MEN1 overexpression are more sensitive to everolimus, a widely used drug in pancreatic neuroendocrine tumors (pNETs) that targets mTOR signaling.

Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]

Target Info

In total 6 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[2]
Target for Ferroptosis	Suppressor
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Responsed Drug	Fatostatin		Investigative	Drug Info
Pathway Response	Cell adhesion molecules			hsa04514
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	After anesthetizing the nude mice with isoflurane inhalation, we injected 1 x 10⁶ U87 cells that were engineered for the expression of luciferase into the right striatum (3.5 mm from the midline of the brain and 2 mm in front of the coronal suture, injection depth of 3 mm from the brain surface) of the nude mice to establish an intracranial xenograft model. For the detection of pharmacokinetics in mice, RhoB-loaded p28-PLGA NPs were injected into the mice (n = 3) through the tail vein. We collected blood samples at predetermined time points, quantified the RhoB concentrations, and plotted them with time. To characterize NPs for GBM treatment, we randomly divided the tumor-bearing mice into four groups (n = 8) treated with PBS, free fatostatin (25 mg/kg), NPs-FAT (fatostatin equivalent dose at 25 mg/kg), and p28-NPs-FAT (fatostatin equivalent dose at 25 mg/kg). After 7 days of tumor inoculation, the treatment was conducted 3 days per week for 4 weeks. In addition, we performed IVIS imaging of intracranial tumors at 1, 3, and 5 weeks after tumor inoculation to observe tumor progression. IVIS was also used to carry out imaging of IR780-loaded NPs. The mice were monitored regularly and euthanized when they exhibited severe neurological symptoms and/or obvious weight loss (>20% of their body weight). We sacrificed a separate cohort of mice five weeks after tumor inoculation for pathological staining (n = 3). Click to Show/Hide
Response regulation	Fatostatin induces ferroptosis by inhibiting the AKT/ mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway.
Experiment 2 Reporting the Ferroptosis Target of This Regulator				[2]
Target for Ferroptosis	Suppressor
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Responsed Drug	Fatostatin		Investigative	Drug Info
Pathway Response	Cell adhesion molecules			hsa04514
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	After anesthetizing the nude mice with isoflurane inhalation, we injected 1 x 10⁶ U87 cells that were engineered for the expression of luciferase into the right striatum (3.5 mm from the midline of the brain and 2 mm in front of the coronal suture, injection depth of 3 mm from the brain surface) of the nude mice to establish an intracranial xenograft model. For the detection of pharmacokinetics in mice, RhoB-loaded p28-PLGA NPs were injected into the mice (n = 3) through the tail vein. We collected blood samples at predetermined time points, quantified the RhoB concentrations, and plotted them with time. To characterize NPs for GBM treatment, we randomly divided the tumor-bearing mice into four groups (n = 8) treated with PBS, free fatostatin (25 mg/kg), NPs-FAT (fatostatin equivalent dose at 25 mg/kg), and p28-NPs-FAT (fatostatin equivalent dose at 25 mg/kg). After 7 days of tumor inoculation, the treatment was conducted 3 days per week for 4 weeks. In addition, we performed IVIS imaging of intracranial tumors at 1, 3, and 5 weeks after tumor inoculation to observe tumor progression. IVIS was also used to carry out imaging of IR780-loaded NPs. The mice were monitored regularly and euthanized when they exhibited severe neurological symptoms and/or obvious weight loss (>20% of their body weight). We sacrificed a separate cohort of mice five weeks after tumor inoculation for pathological staining (n = 3). Click to Show/Hide
Response regulation	Fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway.
Experiment 3 Reporting the Ferroptosis Target of This Regulator				[3]
Target for Ferroptosis	Suppressor
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Responsed Drug	Curcumin		Investigative	Drug Info
Pathway Response	PI3K-Akt signaling pathway			hsa04151
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HCT-8 cells	Ileocecal adenocarcinoma	Homo sapiens	CVCL_2478
Response regulation	Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/ mTOR signaling pathway.
Experiment 4 Reporting the Ferroptosis Target of This Regulator				[3]
Target for Ferroptosis	Suppressor
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Responsed Drug	Curcumin		Investigative	Drug Info
Pathway Response	PI3K-Akt signaling pathway			hsa04151
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HCT-8 cells	Ileocecal adenocarcinoma	Homo sapiens	CVCL_2478
Response regulation	Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/mTOR signaling pathway.
Experiment 5 Reporting the Ferroptosis Target of This Regulator				[4]
Target for Ferroptosis	Suppressor
Responsed Disease	Cerebral ischemia		ICD-11: 8B10	Disease Info
Responsed Drug	Dihydromyricetin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Rats were anesthetized by pentobarbital sodium at a dosage of 40 mg/kg by intraperitoneal injection. Rats were first anchored on to an operating table in the supine position. The fur around the incision was shaved and then disinfected. Subsequently, the neck of each rat was incised in the middle to expose the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA). The proximal end of the CCA and ECA were ligated and severed using a 0.285 mm nylon suture. The suture was inserted from the ECA stump through the ICA to reach the MCA. The MCA was then occluded for 2 h to create ischemic conditions. Next, the nylon suture was slowly pulled out to restore blood flow and simulate reperfusion condition. Click to Show/Hide
Response regulation	Dihydromyricetin (DHM) repressed ferroptosis by inhibiting the SPHK1/ mTOR signaling pathway, thereby alleviating cerebral ischemia reperfusion injury. Moreover, the expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM.
Experiment 6 Reporting the Ferroptosis Target of This Regulator				[9]
Target for Ferroptosis	Suppressor
Responsed Disease	Pancreatic cancer		ICD-11: 2C10	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Autophagy			hsa04140
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	PANC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0480
	MIA PaCa-2 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0428
	SW1990 cells	Pancreatic adenocarcinoma	Homo sapiens	CVCL_1723
In Vivo Model	To generate murine subcutaneous tumors, 5 x 10⁶ PANC1 or MIAPaCa2 cells in 100 ul PBS were injected subcutaneously into the right of the dorsal midline in 6- to 8-week-old athymic nude or B6 mice (female). Once the tumors reached 50-70 mm³ at day 7, mice were randomly allocated into groups and treated with rapamycin (20 mg/kg; i.p., once every other day) in the absence or presence of liproxstatin-1 (10 mg/kg; i.p., once every other day) or hydroxychloroquine (50 mg/kg; i.p., once every other day) for 2 weeks. Click to Show/Hide
Response regulation	The interplay between the signals of mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) modulates autophagy-dependent ferroptosis in human pancreatic cancer cells. Both the classical autophagy inducer rapamycin and the classical ferroptosis activator RSL3 can block MTOR activation and cause GPX4 protein degradation in human pancreatic cancer cells.

Unspecific Target [Unspecific Target]

In total 5 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator				[5]
Responsed Disease	Oesophageal cancer		ICD-11: 2B70	Disease Info
Responsed Drug	Allicin		Investigative	Drug Info
Pathway Response	mTOR signaling pathway			hsa04150
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	TE-1 cells	Esophageal squamous cell carcinoma	Homo sapiens	CVCL_1759
	KYSE-510 cells	Esophageal squamous cell carcinoma	Homo sapiens	CVCL_1354
	HET-1A cells	Normal	Homo sapiens	CVCL_3702
In Vivo Model	All mice were housed in a specific pathogen-free environment under a standard 12 h light-dark cycle at 25 and had ad libitum access to food and water. Approximately 4 x 10⁶ KYSE510 cells in 100 uL of normal saline were subcutaneously injected into the right flank of mice (n = 20 in total). All mice were allocated to a control or 10 mg/kg allicin group (n = 10 per group), as previously described (Suddek 2014). The mice were orally administered allicin or normal saline once daily for 28 days. Click to Show/Hide
Response regulation	In summary, allicin may induce cell death in esophageal squamous cell carcinoma (ESCC) cells by activating AMPK/mTOR-mediated autophagy and ferroptosis. Furthermore, ATG5 and ATG7 expression increased in tumors after allicin treatment. In contrast, NCOA4 expression increased, but the protein level of FTH1 and TfR1 decreased in tumors after allicin treatment.
Experiment 2 Reporting the Ferroptosis Target of This Regulator				[6]
Responsed Disease	Corpus uteri cancer		ICD-11: 2C76	Disease Info
Responsed Drug	Amentoflavone		Investigative	Drug Info
Pathway Response	mTOR signaling pathway			hsa04150
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	hESCs (Human endometrial stromal cells)
	KLE cells	Endometrial adenocarcinoma	Homo sapiens	CVCL_1329
Response regulation	Amentoflavone inhibited the viability and proliferation of endometrial carcinoma cells (KLE) cells but promoted apoptosis and ferroptosis. The expressions of ROS and AMPK were increased, while mTOR expression was decreased in AF-treated KLE cells. NAC reversed the effects of AF on biological behaviors of KLE cells by inactivating ROS/AMPK/mTOR signaling.
Experiment 3 Reporting the Ferroptosis Target of This Regulator				[7]
Responsed Disease	Hereditary Leiomyomatosis		ICD-11: 2C90	Disease Info
Responsed Drug	Everolimus		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Glutathione metabolism			hsa00480
	mTOR signaling pathway			hsa04150
Cell Process	Cell ferroptosis
In Vitro Model	ACHN cells	Papillary renal cell carcinoma	Homo sapiens	CVCL_1067
	Caki-1 cells	Clear cell renal cell carcinoma	Homo sapiens	CVCL_0234
	HEK293 cells	Normal	Homo sapiens	CVCL_0045
Response regulation	Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in Renal cell carcinoma cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment.
Experiment 4 Reporting the Ferroptosis Target of This Regulator				[8]
Responsed Disease	Hereditary Leiomyomatosis		ICD-11: 2C90	Disease Info
Responsed Drug	Rapamycin		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	UOK262 cells	Hereditary leiomyomatosis	Homo sapiens	CVCL_1D72
	NCCFH1 (Human hereditary leiomyomatosis and renal cell cancer cells)
In Vivo Model	Ten million NCCFH1 cells suspended in a 1:1 ratio of PBS:Matrigel were injected into the right flank of each animal. Tumors were measured twice a week using a digital caliper, and tumor volumes were calculated according to the volume of an ellipsoid. When mean tumor volumes reached 100 mm³, an equal number of male and female mice were randomly assigned into four different groups. Thirty three of the 40 mice used in the experiment developed tumors. Thus, the final group assignment was as follow: vehicle (control group, n = 6, 3 female & 3 male), rapamycin (rapamycin only group, n = 7, 4 female & 3 male), Cyst(e)inase (Cyst(e)inase only group, n = 10, 5 female & 5 male), rapamycin+Cyst(e)inase (combination group, n = 10, 5 female & 5 male). Treatments were administered once every three days via intraperitoneal injection of either vehicle (Phosphate buffered saline containing 30% PEG300), rapamycin (0.6 mg/ml suspended in vehicle, injection dose = 0.6 mg per mouse), Cyst(e)inase (7.1 mg/ml suspended in vehicle, injection dose = 7.1 mg per mouse), and rapamycin+Cyst(e)inase combination (0.6 mg/ml rapamycin, 7.1 mg/ml Cyst(e)inase suspended in vehicle. Click to Show/Hide
Response regulation	Rapamycin treatment inhibited MTOR signaling. And it is possible to induce ferroptosis in an hereditary leiomyomatosis and renal cell cancer (HLRCC) tumor model in vivo using a combination of rapamycin and Cyst(e)inase.
Experiment 5 Reporting the Ferroptosis Target of This Regulator				[10]
Responsed Disease	Lung cancer		ICD-11: 2C25	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Autophagy			hsa04140
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	PC-9 cells	Lung adenocarcinoma	Homo sapiens	CVCL_B260
	A-549 cells	Lung adenocarcinoma	Homo sapiens	CVCL_0023
In Vivo Model	The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Second Xiangya Hospital following the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Briefly, female BALB/c nude mice at six weeks were obtained from Hunan SJA Laboratory Animal Co. Ltd. (Hunan, China) and kept in a specific pathogen-free environment. The mice were injected subcutaneously with 2 x 10⁶ indicated cells into the left or right flank for 21 days (PC9) or 28 days (A549) post-implantation. At the end of the experiment, the tumours were dissected and weighed. Click to Show/Hide
Response regulation	LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes lung adenocarcinoma (LUAD) autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner.

Glioblastoma [ICD-11: 2A00]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[2]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Fatostatin		Investigative	Drug Info
Pathway Response	Cell adhesion molecules			hsa04514
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	After anesthetizing the nude mice with isoflurane inhalation, we injected 1 x 10⁶ U87 cells that were engineered for the expression of luciferase into the right striatum (3.5 mm from the midline of the brain and 2 mm in front of the coronal suture, injection depth of 3 mm from the brain surface) of the nude mice to establish an intracranial xenograft model. For the detection of pharmacokinetics in mice, RhoB-loaded p28-PLGA NPs were injected into the mice (n = 3) through the tail vein. We collected blood samples at predetermined time points, quantified the RhoB concentrations, and plotted them with time. To characterize NPs for GBM treatment, we randomly divided the tumor-bearing mice into four groups (n = 8) treated with PBS, free fatostatin (25 mg/kg), NPs-FAT (fatostatin equivalent dose at 25 mg/kg), and p28-NPs-FAT (fatostatin equivalent dose at 25 mg/kg). After 7 days of tumor inoculation, the treatment was conducted 3 days per week for 4 weeks. In addition, we performed IVIS imaging of intracranial tumors at 1, 3, and 5 weeks after tumor inoculation to observe tumor progression. IVIS was also used to carry out imaging of IR780-loaded NPs. The mice were monitored regularly and euthanized when they exhibited severe neurological symptoms and/or obvious weight loss (>20% of their body weight). We sacrificed a separate cohort of mice five weeks after tumor inoculation for pathological staining (n = 3). Click to Show/Hide
Response regulation	Fatostatin induces ferroptosis by inhibiting the AKT/ mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[2]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Fatostatin		Investigative	Drug Info
Pathway Response	Cell adhesion molecules			hsa04514
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	After anesthetizing the nude mice with isoflurane inhalation, we injected 1 x 10⁶ U87 cells that were engineered for the expression of luciferase into the right striatum (3.5 mm from the midline of the brain and 2 mm in front of the coronal suture, injection depth of 3 mm from the brain surface) of the nude mice to establish an intracranial xenograft model. For the detection of pharmacokinetics in mice, RhoB-loaded p28-PLGA NPs were injected into the mice (n = 3) through the tail vein. We collected blood samples at predetermined time points, quantified the RhoB concentrations, and plotted them with time. To characterize NPs for GBM treatment, we randomly divided the tumor-bearing mice into four groups (n = 8) treated with PBS, free fatostatin (25 mg/kg), NPs-FAT (fatostatin equivalent dose at 25 mg/kg), and p28-NPs-FAT (fatostatin equivalent dose at 25 mg/kg). After 7 days of tumor inoculation, the treatment was conducted 3 days per week for 4 weeks. In addition, we performed IVIS imaging of intracranial tumors at 1, 3, and 5 weeks after tumor inoculation to observe tumor progression. IVIS was also used to carry out imaging of IR780-loaded NPs. The mice were monitored regularly and euthanized when they exhibited severe neurological symptoms and/or obvious weight loss (>20% of their body weight). We sacrificed a separate cohort of mice five weeks after tumor inoculation for pathological staining (n = 3). Click to Show/Hide
Response regulation	Fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway.

Colorectal cancer [ICD-11: 2B91]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[3]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Curcumin		Investigative	Drug Info
Pathway Response	PI3K-Akt signaling pathway			hsa04151
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HCT-8 cells	Ileocecal adenocarcinoma	Homo sapiens	CVCL_2478
Response regulation	Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/ mTOR signaling pathway.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[3]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Curcumin		Investigative	Drug Info
Pathway Response	PI3K-Akt signaling pathway			hsa04151
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HCT-8 cells	Ileocecal adenocarcinoma	Homo sapiens	CVCL_2478
Response regulation	Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/mTOR signaling pathway.

Pancreatic cancer [ICD-11: 2C10]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[1]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Everolimus		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	BON-1 cells	Pancreatic serotonin-producing neuroendocrine tumor	Homo sapiens	CVCL_3985
	QGP-1 cells	Pancreatic somatostatinoma	Homo sapiens	CVCL_3143
Response regulation	The negative correlation between MEN1 and SCD1 is further verified in clinical specimens. Furthermore, BON-1 and QGP-1 cells with MEN1 overexpression are more sensitive to everolimus, a widely used drug in pancreatic neuroendocrine tumors (pNETs) that targets mTOR signaling.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[9]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
	Autophagy			hsa04140
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	PANC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0480
	MIA PaCa-2 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0428
	SW1990 cells	Pancreatic adenocarcinoma	Homo sapiens	CVCL_1723
In Vivo Model	To generate murine subcutaneous tumors, 5 x 10⁶ PANC1 or MIAPaCa2 cells in 100 ul PBS were injected subcutaneously into the right of the dorsal midline in 6- to 8-week-old athymic nude or B6 mice (female). Once the tumors reached 50-70 mm³ at day 7, mice were randomly allocated into groups and treated with rapamycin (20 mg/kg; i.p., once every other day) in the absence or presence of liproxstatin-1 (10 mg/kg; i.p., once every other day) or hydroxychloroquine (50 mg/kg; i.p., once every other day) for 2 weeks. Click to Show/Hide
Response regulation	The interplay between the signals of mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) modulates autophagy-dependent ferroptosis in human pancreatic cancer cells. Both the classical autophagy inducer rapamycin and the classical ferroptosis activator RSL3 can block MTOR activation and cause GPX4 protein degradation in human pancreatic cancer cells.

Cerebral ischemia [ICD-11: 8B10]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[4]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Dihydromyricetin		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Rats were anesthetized by pentobarbital sodium at a dosage of 40 mg/kg by intraperitoneal injection. Rats were first anchored on to an operating table in the supine position. The fur around the incision was shaved and then disinfected. Subsequently, the neck of each rat was incised in the middle to expose the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA). The proximal end of the CCA and ECA were ligated and severed using a 0.285 mm nylon suture. The suture was inserted from the ECA stump through the ICA to reach the MCA. The MCA was then occluded for 2 h to create ischemic conditions. Next, the nylon suture was slowly pulled out to restore blood flow and simulate reperfusion condition. Click to Show/Hide
Response regulation	Dihydromyricetin (DHM) repressed ferroptosis by inhibiting the SPHK1/ mTOR signaling pathway, thereby alleviating cerebral ischemia reperfusion injury. Moreover, the expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM.

Oesophageal cancer [ICD-11: 2B70]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[5]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Allicin		Investigative	Drug Info
Pathway Response	mTOR signaling pathway			hsa04150
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	TE-1 cells	Esophageal squamous cell carcinoma	Homo sapiens	CVCL_1759
	KYSE-510 cells	Esophageal squamous cell carcinoma	Homo sapiens	CVCL_1354
	HET-1A cells	Normal	Homo sapiens	CVCL_3702
In Vivo Model	All mice were housed in a specific pathogen-free environment under a standard 12 h light-dark cycle at 25 and had ad libitum access to food and water. Approximately 4 x 10⁶ KYSE510 cells in 100 uL of normal saline were subcutaneously injected into the right flank of mice (n = 20 in total). All mice were allocated to a control or 10 mg/kg allicin group (n = 10 per group), as previously described (Suddek 2014). The mice were orally administered allicin or normal saline once daily for 28 days. Click to Show/Hide
Response regulation	In summary, allicin may induce cell death in esophageal squamous cell carcinoma (ESCC) cells by activating AMPK/mTOR-mediated autophagy and ferroptosis. Furthermore, ATG5 and ATG7 expression increased in tumors after allicin treatment. In contrast, NCOA4 expression increased, but the protein level of FTH1 and TfR1 decreased in tumors after allicin treatment.

Corpus uteri cancer [ICD-11: 2C76]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[6]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Amentoflavone		Investigative	Drug Info
Pathway Response	mTOR signaling pathway			hsa04150
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	hESCs (Human endometrial stromal cells)
	KLE cells	Endometrial adenocarcinoma	Homo sapiens	CVCL_1329
Response regulation	Amentoflavone inhibited the viability and proliferation of endometrial carcinoma cells (KLE) cells but promoted apoptosis and ferroptosis. The expressions of ROS and AMPK were increased, while mTOR expression was decreased in AF-treated KLE cells. NAC reversed the effects of AF on biological behaviors of KLE cells by inactivating ROS/AMPK/mTOR signaling.

Hereditary Leiomyomatosis [ICD-11: 2C90]

Disease Info

In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[7]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Everolimus		Investigative	Drug Info
Pathway Response	Ferroptosis			hsa04216
	Glutathione metabolism			hsa00480
	mTOR signaling pathway			hsa04150
Cell Process	Cell ferroptosis
In Vitro Model	ACHN cells	Papillary renal cell carcinoma	Homo sapiens	CVCL_1067
	Caki-1 cells	Clear cell renal cell carcinoma	Homo sapiens	CVCL_0234
	HEK293 cells	Normal	Homo sapiens	CVCL_0045
Response regulation	Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in Renal cell carcinoma cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment.
Experiment 2 Reporting the Ferroptosis-centered Disease Response				[8]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Responsed Drug	Rapamycin		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	UOK262 cells	Hereditary leiomyomatosis	Homo sapiens	CVCL_1D72
	NCCFH1 (Human hereditary leiomyomatosis and renal cell cancer cells)
In Vivo Model	Ten million NCCFH1 cells suspended in a 1:1 ratio of PBS:Matrigel were injected into the right flank of each animal. Tumors were measured twice a week using a digital caliper, and tumor volumes were calculated according to the volume of an ellipsoid. When mean tumor volumes reached 100 mm³, an equal number of male and female mice were randomly assigned into four different groups. Thirty three of the 40 mice used in the experiment developed tumors. Thus, the final group assignment was as follow: vehicle (control group, n = 6, 3 female & 3 male), rapamycin (rapamycin only group, n = 7, 4 female & 3 male), Cyst(e)inase (Cyst(e)inase only group, n = 10, 5 female & 5 male), rapamycin+Cyst(e)inase (combination group, n = 10, 5 female & 5 male). Treatments were administered once every three days via intraperitoneal injection of either vehicle (Phosphate buffered saline containing 30% PEG300), rapamycin (0.6 mg/ml suspended in vehicle, injection dose = 0.6 mg per mouse), Cyst(e)inase (7.1 mg/ml suspended in vehicle, injection dose = 7.1 mg per mouse), and rapamycin+Cyst(e)inase combination (0.6 mg/ml rapamycin, 7.1 mg/ml Cyst(e)inase suspended in vehicle. Click to Show/Hide
Response regulation	Rapamycin treatment inhibited MTOR signaling. And it is possible to induce ferroptosis in an hereditary leiomyomatosis and renal cell cancer (HLRCC) tumor model in vivo using a combination of rapamycin and Cyst(e)inase.

Lung cancer [ICD-11: 2C25]

Disease Info

In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response				[10]
Target Regulator	Serine/threonine-protein kinase mTOR (MTOR)		Protein coding	Regulator Info
Pathway Response	Fatty acid metabolism			hsa01212
	Autophagy			hsa04140
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	PC-9 cells	Lung adenocarcinoma	Homo sapiens	CVCL_B260
	A-549 cells	Lung adenocarcinoma	Homo sapiens	CVCL_0023
In Vivo Model	The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Second Xiangya Hospital following the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Briefly, female BALB/c nude mice at six weeks were obtained from Hunan SJA Laboratory Animal Co. Ltd. (Hunan, China) and kept in a specific pathogen-free environment. The mice were injected subcutaneously with 2 x 10⁶ indicated cells into the left or right flank for 21 days (PC9) or 28 days (A549) post-implantation. At the end of the experiment, the tumours were dissected and weighed. Click to Show/Hide
Response regulation	LINC00551 acts as a competing endogenous RNA (ceRNA) and binds with miR-4328 which up-regulates the target DNA damage-inducible transcript 4 (DDIT4). DDIT4 inhibits the activity of mTOR, promotes lung adenocarcinoma (LUAD) autophagy, and then promotes the ferroptosis of LUAD cells in an autophagy-dependent manner.

Curcumin [Investigative]

Drug Info

In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[3]
Drug for Ferroptosis	Inducer
Response Target	Phospholipid hydroperoxide glutathione peroxidase (GPX4)		Suppressor	Target Info
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Pathway Response	PI3K-Akt signaling pathway			hsa04151
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HCT-8 cells	Ileocecal adenocarcinoma	Homo sapiens	CVCL_2478
Response regulation	Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/ mTOR signaling pathway.
Experiment 2 Reporting the Ferroptosis-centered Drug Response				[3]
Drug for Ferroptosis	Inducer
Response Target	Phospholipid hydroperoxide glutathione peroxidase (GPX4)		Suppressor	Target Info
Responsed Disease	Colorectal cancer		ICD-11: 2B91	Disease Info
Pathway Response	PI3K-Akt signaling pathway			hsa04151
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HCT-8 cells	Ileocecal adenocarcinoma	Homo sapiens	CVCL_2478
Response regulation	Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/mTOR signaling pathway.

Dihydromyricetin [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[4]
Drug for Ferroptosis	Suppressor
Response Target	Phospholipid hydroperoxide glutathione peroxidase (GPX4)		Suppressor	Target Info
Responsed Disease	Cerebral ischemia		ICD-11: 8B10	Disease Info
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	Rats were anesthetized by pentobarbital sodium at a dosage of 40 mg/kg by intraperitoneal injection. Rats were first anchored on to an operating table in the supine position. The fur around the incision was shaved and then disinfected. Subsequently, the neck of each rat was incised in the middle to expose the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA). The proximal end of the CCA and ECA were ligated and severed using a 0.285 mm nylon suture. The suture was inserted from the ECA stump through the ICA to reach the MCA. The MCA was then occluded for 2 h to create ischemic conditions. Next, the nylon suture was slowly pulled out to restore blood flow and simulate reperfusion condition. Click to Show/Hide
Response regulation	Dihydromyricetin (DHM) repressed ferroptosis by inhibiting the SPHK1/ mTOR signaling pathway, thereby alleviating cerebral ischemia reperfusion injury. Moreover, the expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM.

Everolimus [Investigative]

Drug Info

In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[1]
Drug for Ferroptosis	Inducer
Response Target	Stearoyl-CoA desaturase (SCD)		Suppressor	Target Info
Responsed Disease	Pancreatic cancer		ICD-11: 2C10	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	BON-1 cells	Pancreatic serotonin-producing neuroendocrine tumor	Homo sapiens	CVCL_3985
In Vitro Model	QGP-1 cells	Pancreatic somatostatinoma	Homo sapiens	CVCL_3143
Response regulation	The negative correlation between MEN1 and SCD1 is further verified in clinical specimens. Furthermore, BON-1 and QGP-1 cells with MEN1 overexpression are more sensitive to everolimus, a widely used drug in pancreatic neuroendocrine tumors (pNETs) that targets mTOR signaling.
Experiment 2 Reporting the Ferroptosis-centered Drug Response				[7]
Drug for Ferroptosis	Inducer
Response Target	Unspecific Target
Responsed Disease	Hereditary Leiomyomatosis		ICD-11: 2C90	Disease Info
Pathway Response	Ferroptosis			hsa04216
	Glutathione metabolism			hsa00480
	mTOR signaling pathway			hsa04150
Cell Process	Cell ferroptosis
In Vitro Model	ACHN cells	Papillary renal cell carcinoma	Homo sapiens	CVCL_1067
	Caki-1 cells	Clear cell renal cell carcinoma	Homo sapiens	CVCL_0234
	HEK293 cells	Normal	Homo sapiens	CVCL_0045
Response regulation	Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in Renal cell carcinoma cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment.

Fatostatin [Investigative]

Drug Info

In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[2]
Drug for Ferroptosis	Inducer
Response Target	Phospholipid hydroperoxide glutathione peroxidase (GPX4)		Suppressor	Target Info
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Pathway Response	Cell adhesion molecules			hsa04514
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	After anesthetizing the nude mice with isoflurane inhalation, we injected 1 x 10⁶ U87 cells that were engineered for the expression of luciferase into the right striatum (3.5 mm from the midline of the brain and 2 mm in front of the coronal suture, injection depth of 3 mm from the brain surface) of the nude mice to establish an intracranial xenograft model. For the detection of pharmacokinetics in mice, RhoB-loaded p28-PLGA NPs were injected into the mice (n = 3) through the tail vein. We collected blood samples at predetermined time points, quantified the RhoB concentrations, and plotted them with time. To characterize NPs for GBM treatment, we randomly divided the tumor-bearing mice into four groups (n = 8) treated with PBS, free fatostatin (25 mg/kg), NPs-FAT (fatostatin equivalent dose at 25 mg/kg), and p28-NPs-FAT (fatostatin equivalent dose at 25 mg/kg). After 7 days of tumor inoculation, the treatment was conducted 3 days per week for 4 weeks. In addition, we performed IVIS imaging of intracranial tumors at 1, 3, and 5 weeks after tumor inoculation to observe tumor progression. IVIS was also used to carry out imaging of IR780-loaded NPs. The mice were monitored regularly and euthanized when they exhibited severe neurological symptoms and/or obvious weight loss (>20% of their body weight). We sacrificed a separate cohort of mice five weeks after tumor inoculation for pathological staining (n = 3). Click to Show/Hide
Response regulation	Fatostatin induces ferroptosis by inhibiting the AKT/ mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway.
Experiment 2 Reporting the Ferroptosis-centered Drug Response				[2]
Drug for Ferroptosis	Inducer
Response Target	Phospholipid hydroperoxide glutathione peroxidase (GPX4)		Suppressor	Target Info
Responsed Disease	Glioblastoma		ICD-11: 2A00	Disease Info
Pathway Response	Cell adhesion molecules			hsa04514
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	U87 MG-Red-Fluc cells	Glioblastoma	Homo sapiens	CVCL_5J12
	U-251MG cells	Astrocytoma	Homo sapiens	CVCL_0021
In Vivo Model	After anesthetizing the nude mice with isoflurane inhalation, we injected 1 x 10⁶ U87 cells that were engineered for the expression of luciferase into the right striatum (3.5 mm from the midline of the brain and 2 mm in front of the coronal suture, injection depth of 3 mm from the brain surface) of the nude mice to establish an intracranial xenograft model. For the detection of pharmacokinetics in mice, RhoB-loaded p28-PLGA NPs were injected into the mice (n = 3) through the tail vein. We collected blood samples at predetermined time points, quantified the RhoB concentrations, and plotted them with time. To characterize NPs for GBM treatment, we randomly divided the tumor-bearing mice into four groups (n = 8) treated with PBS, free fatostatin (25 mg/kg), NPs-FAT (fatostatin equivalent dose at 25 mg/kg), and p28-NPs-FAT (fatostatin equivalent dose at 25 mg/kg). After 7 days of tumor inoculation, the treatment was conducted 3 days per week for 4 weeks. In addition, we performed IVIS imaging of intracranial tumors at 1, 3, and 5 weeks after tumor inoculation to observe tumor progression. IVIS was also used to carry out imaging of IR780-loaded NPs. The mice were monitored regularly and euthanized when they exhibited severe neurological symptoms and/or obvious weight loss (>20% of their body weight). We sacrificed a separate cohort of mice five weeks after tumor inoculation for pathological staining (n = 3). Click to Show/Hide
Response regulation	Fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway.

Allicin [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[5]
Drug for Ferroptosis	Inducer
Response Target	Unspecific Target
Responsed Disease	Oesophageal cancer		ICD-11: 2B70	Disease Info
Pathway Response	mTOR signaling pathway			hsa04150
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell autophagy
In Vitro Model	TE-1 cells	Esophageal squamous cell carcinoma	Homo sapiens	CVCL_1759
	KYSE-510 cells	Esophageal squamous cell carcinoma	Homo sapiens	CVCL_1354
	HET-1A cells	Normal	Homo sapiens	CVCL_3702
In Vivo Model	All mice were housed in a specific pathogen-free environment under a standard 12 h light-dark cycle at 25 and had ad libitum access to food and water. Approximately 4 x 10⁶ KYSE510 cells in 100 uL of normal saline were subcutaneously injected into the right flank of mice (n = 20 in total). All mice were allocated to a control or 10 mg/kg allicin group (n = 10 per group), as previously described (Suddek 2014). The mice were orally administered allicin or normal saline once daily for 28 days. Click to Show/Hide
Response regulation	In summary, allicin may induce cell death in esophageal squamous cell carcinoma (ESCC) cells by activating AMPK/mTOR-mediated autophagy and ferroptosis. Furthermore, ATG5 and ATG7 expression increased in tumors after allicin treatment. In contrast, NCOA4 expression increased, but the protein level of FTH1 and TfR1 decreased in tumors after allicin treatment.

Amentoflavone [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[6]
Drug for Ferroptosis	Inducer
Response Target	Unspecific Target
Responsed Disease	Corpus uteri cancer		ICD-11: 2C76	Disease Info
Pathway Response	mTOR signaling pathway			hsa04150
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell apoptosis
	Cell proliferation
In Vitro Model	hESCs (Human endometrial stromal cells)
	KLE cells	Endometrial adenocarcinoma	Homo sapiens	CVCL_1329
Response regulation	Amentoflavone inhibited the viability and proliferation of endometrial carcinoma cells (KLE) cells but promoted apoptosis and ferroptosis. The expressions of ROS and AMPK were increased, while mTOR expression was decreased in AF-treated KLE cells. NAC reversed the effects of AF on biological behaviors of KLE cells by inactivating ROS/AMPK/mTOR signaling.

Rapamycin [Investigative]

Drug Info

In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response				[8]
Drug for Ferroptosis	Inducer
Response Target	Unspecific Target
Responsed Disease	Hereditary Leiomyomatosis		ICD-11: 2C90	Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	UOK262 cells	Hereditary leiomyomatosis	Homo sapiens	CVCL_1D72
	NCCFH1 (Human hereditary leiomyomatosis and renal cell cancer cells)
In Vivo Model	Ten million NCCFH1 cells suspended in a 1:1 ratio of PBS:Matrigel were injected into the right flank of each animal. Tumors were measured twice a week using a digital caliper, and tumor volumes were calculated according to the volume of an ellipsoid. When mean tumor volumes reached 100 mm³, an equal number of male and female mice were randomly assigned into four different groups. Thirty three of the 40 mice used in the experiment developed tumors. Thus, the final group assignment was as follow: vehicle (control group, n = 6, 3 female & 3 male), rapamycin (rapamycin only group, n = 7, 4 female & 3 male), Cyst(e)inase (Cyst(e)inase only group, n = 10, 5 female & 5 male), rapamycin+Cyst(e)inase (combination group, n = 10, 5 female & 5 male). Treatments were administered once every three days via intraperitoneal injection of either vehicle (Phosphate buffered saline containing 30% PEG300), rapamycin (0.6 mg/ml suspended in vehicle, injection dose = 0.6 mg per mouse), Cyst(e)inase (7.1 mg/ml suspended in vehicle, injection dose = 7.1 mg per mouse), and rapamycin+Cyst(e)inase combination (0.6 mg/ml rapamycin, 7.1 mg/ml Cyst(e)inase suspended in vehicle. Click to Show/Hide
Response regulation	Rapamycin treatment inhibited MTOR signaling. And it is possible to induce ferroptosis in an hereditary leiomyomatosis and renal cell cancer (HLRCC) tumor model in vivo using a combination of rapamycin and Cyst(e)inase.

References

Ref 1	MEN1 promotes ferroptosis by inhibiting mTOR-SCD1 axis in pancreatic neuroendocrine tumors. Acta Biochim Biophys Sin (Shanghai). 2022 Nov 25;54(11):1599-1609. doi: 10.3724/abbs.2022162.
Ref 2	Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. Cell Death Dis. 2023 Mar 25;14(3):211. doi: 10.1038/s41419-023-05738-8.
Ref 3	Curcumin Represses Colorectal Cancer Cell Proliferation by Triggering Ferroptosis via PI3K/Akt/mTOR Signaling. Nutr Cancer. 2023;75(2):726-733. doi: 10.1080/01635581.2022.2139398. Epub 2022 Nov 8.
Ref 4	Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis. Drug Des Devel Ther. 2022 Sep 11;16:3071-3085. doi: 10.2147/DDDT.S378786. eCollection 2022.
Ref 5	Allicin promotes autophagy and ferroptosis in esophageal squamous cell carcinoma by activating AMPK/mTOR signaling. Heliyon. 2022 Oct 12;8(10):e11005. doi: 10.1016/j.heliyon.2022.e11005. eCollection 2022 Oct.
Ref 6	Amentoflavone promotes ferroptosis by regulating reactive oxygen species (ROS) /5'AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) to inhibit the malignant progression of endometrial carcinoma cells. Bioengineered. 2022 May;13(5):13269-13279. doi: 10.1080/21655979.2022.2079256.
Ref 7	Everolimus accelerates Erastin and RSL3-induced ferroptosis in renal cell carcinoma. Gene. 2022 Jan 30;809:145992. doi: 10.1016/j.gene.2021.145992. Epub 2021 Oct 11.
Ref 8	Cyst(e)inase-Rapamycin Combination Induces Ferroptosis in Both In Vitro and In Vivo Models of Hereditary Leiomyomatosis and Renal Cell Cancer. Mol Cancer Ther. 2022 Mar 1;21(3):419-426. doi: 10.1158/1535-7163.MCT-21-0661.
Ref 9	Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death. Cancer Gene Ther. 2021 Feb;28(1-2):55-63. doi: 10.1038/s41417-020-0182-y. Epub 2020 May 27.
Ref 10	Overexpression of LINC00551 promotes autophagy-dependent ferroptosis of lung adenocarcinoma via upregulating DDIT4 by sponging miR-4328. PeerJ. 2022 Oct 12;10:e14180. doi: 10.7717/peerj.14180. eCollection 2022.

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Prof. Shuiping Liu