Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0049)
Name
Metformin
Synonyms
metformin; 657-24-9; 1,1-Dimethylbiguanide; N,N-dimethylimidodicarbonimidic diamide; Fluamine; Metiguanide; Dimethylbiguanide; Flumamine; Gliguanid; Haurymelin; Metformine; Melbin; Imidodicarbonimidic diamide, N,N-dimethyl-; N,N-Dimethylbiguanide; Islotin; Dimethyldiguanide; N1,N1-Dimethylbiguanide; DMGG; NNDG; N,N-Dimethyldiguanide; Diabetosan; Metformina; Metforminum; Glumetza; Glifage; Siofor; LA-6023; BIGUANIDE, 1,1-DIMETHYL-; 3-(diaminomethylidene)-1,1-dimethylguanidine; Dimethylbiguanid; 1,1-Dimethyl biguanide; C4H11N5; Metformin extended release; EINECS 211-517-8; CCRIS 9321; CHEBI:6801; DTXSID2023270; UNII-9100L32L2N; 9100L32L2N; CHEMBL1431; DTXCID803270; Imidodicarbonimidic diamide-, N,N-dimethyl-; Metformina [DCIT]; Metformina [Spanish]; Dimethylguanylguanidine; Metformine [INN-French]; Metforminum [INN-Latin]; Metformin [USAN:INN:BAN]; Gen-Metformin; MLS000028493; Nu-Metformin; [14C]metformin; [14C]-metformin; Metformin (USAN/INN); NCGC00016564-01; SMR000058277; CAS-1115-70-4; N,N-dimethylguanylguanidine; Dianben; Obimet; N-dimethylbiguanide; Metforminum (Latin); DMBG; Glucophage (Salt/Mix); METFORMIN [INN]; n',n'-dimethylbiguanide; METFORMIN [MI]; METFORMIN [USAN]; Prestwick0_000004; Prestwick1_000004; Prestwick2_000004; Prestwick3_000004; METFORMIN [VANDF]; N,N-Dimethylguanylguanidin; METFORMIN [WHO-DD]; SCHEMBL8944; BSPBio_000007; BSPBio_002314; KBioGR_002310; KBioSS_002312; cid_14219; LA 6023 (Salt/Mix); BIDD:GT0697; SPBio_001928; N(1),N(1)-dimethylbiguanide; BPBio1_000009; GTPL4503; GTPL4779; SCHEMBL9913821; SCHEMBL10276396; BDBM57047; KBio2_002310; KBio2_004878; KBio2_007446; KBio3_002790; A10BA02; cMAP_000016; HMS2089D19; HY-B0627; Tox21_302370; BBL012337; BDBM50229665; HSCI1_000295; MFCD00242652; NSC813213; s5958; STK011633; STL483693; STL484070; N,N-Dimethyltriimidodicarbonic diamide; AKOS000121065; AKOS005206848; AKOS015966566; CCG-102605; DB00331; N,N-Diethyl-Imidodicarbonimidic diamide; NSC-813213; 3-carbamimidoyl-1,1-dimethyl-guanidine; NCGC00016564-02; NCGC00016564-03; NCGC00016564-05; NCGC00016564-07; NCGC00188959-01; NCGC00255255-01; AC-32484; AS-65365; CAS-657-24-9; SBI-0206876.P001; 1-carbamimidamido-N,N-dimethylmethanimidamide; CS-0009563; FT-0628266; EN300-23696; A19551; C07151; D04966; D72476; EN300-746417; Q19484; (E)-3-[Amino(dimethylamino)methylidene]guanidine; 1-[(E)-amino(dimethylamino)methylidene]guanidine; W-109589; {[amino(dimethylamino)methylidene]amino}methanimidamide; BRD-K79602928-003-04-1; BRD-K79602928-003-08-2; 3-(diaminomethylene)-1,1-dimethyl-guanidine;hydrochloride; [(E)-[AMINO(DIMETHYLAMINO)METHYLIDENE]AMINO]METHANIMIDAMIDE; 3-[bis(azanyl)methylidene]-1,1-dimethyl-guanidine;hydrochloride; MF8

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Structure
Formula
C4H11N5
IUPAC Name
3-(diaminomethylidene)-1,1-dimethylguanidine
Canonical SMILES
CN(C)C(=N)N=C(N)N
InChI
InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
InChIKey
XZWYZXLIPXDOLR-UHFFFAOYSA-N
PubChem CID
4091
Full List of Ferroptosis Target Related to This Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Regulator hsa-miR-324-3p (miRNA) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
In Vivo Model
Six-week-old athymic nude mice were obtained from Nanjing Biomedical Research Institute of Nanjing University (Nanjing, China). Mice were divided into five groups: sham group, metformin group, metformin + NC group, metformin + miR-324-3p overexpression group, and metformin + miR-324-3p knockdown group (n = 6 in each group). Mice were injected with 3 x 106 MDA-MB-231 cells subcutaneously into the right flank. For the miR-324-3p overexpression or knockdown in the mice, two groups of mice were treated with miR-324-3p overexpression or knockdown lentivirus (GenePharma), respectively, by intratumoral injection of 50 ul of lentivirus (4 x 107 IU/ml) after the tumor cell injection. One day after tumor cell inoculation, the sham-treated group was treated with PBS and metformin-treated groups were treated with 200 mg/kg metformin every 2 days through intraperitoneal injection.

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Response regulation Metformin promotes ferroptosis of breast cancer by targeting the miR-324-3p/GPX4 axis. The effect of miR-324-3p was mediated by directly targeting glutathione peroxidase 4 (GPX4). Metformin could act as a potential anti-cancer agent through the induction of ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [5]
Target for Ferroptosis Suppressor
Responsed Disease Ovarian dysfunction ICD-11: 5A80
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vivo Model
n = 6 blank control group was created. The mice in the control group were fed regular food and gavaged with normal saline daily. The mice in the control group were given a high-fat diet and 1 mg/kg of letrozole via gavage for 21 days to establish a PCOS model of insulin resistance and hyperandrogenism. The mice, after successful modeling, were randomly divided into PCOS group and metformin group (n = 6). During the treatment period, the control group continued to be fed with normal feed and given normal saline; the PCOS group was fed with continuous high-fat feed and given letrozole (1 mg/kg/day) by intragastric administration, and the metformin group was given metformin by intragastric administration (200 mg/kg/day). After 30 days of treatment, the experimental mice were euthanized, serum was collected, one mouse ovary was collected for histological examination, and the other was stored in a -80 refrigerator for molecular biology experimental research.

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Response regulation Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. Metformin could regulate ferroptosis to improve polycystic ovary syndrome via the SIRT3/AMPK/mTOR pathway.
Cystine/glutamate transporter (SLC7A11)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Responsed Regulator Protein FAM98A (FAM98A) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model RKO cells Colon carcinoma Homo sapiens CVCL_0504
SW480 cells Colon adenocarcinoma Homo sapiens CVCL_0546
SW620 cells Colon adenocarcinoma Homo sapiens CVCL_0547
LoVo cells Colon adenocarcinoma Homo sapiens CVCL_0399
Caco-2 cells Colon adenocarcinoma Homo sapiens CVCL_0025
HCT 15 cells Colon adenocarcinoma Homo sapiens CVCL_0292
DLD-1 cells Colon adenocarcinoma Homo sapiens CVCL_0248
FHC cells Normal Homo sapiens CVCL_3688
In Vivo Model
A total 1 x 106 SW620-vector or SW620-FAM98A cells were suspended in 100 ul PBS and injected s.c. into the back of 4- to 6-week-old male BALB/cnude mice (Laboratory Animal Unit, Southern Medical University, China). The sizes of the resulting tumors were measured weekly. Tumor volumes were calculated as follows: total tumor volume (mm3) = (Length x Width2)/2, where Length is the longest length. When the tumor sizes reached about 200 mm3, nude mice in the four groups were given PBS or 5-FU treatment (30 mg/kg, intraperitoneal injection, twice a week), respectively. Nude mice were maintained in a barrier facility in racks filtered with a high-efficiency particulate air filter.

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Response regulation The expressions of FAM98A and SLC7A11 were also downregulated after metformin treatment. And FAM98A is predominantly expressed in the colorectal cancer tissues and high FAM98A expression is usually accompanied by the high expression of SLC7A11, which usually means ferroptosis resistance.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Regulator Ubiquitin-fold modifier 1 (UFM1) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
T-47D cells Invasive breast carcinoma Homo sapiens CVCL_0553
HCC1937 cells Breast ductal carcinoma Homo sapiens CVCL_0290
Bcap37 cells Breast carcinoma Homo sapiens CVCL_0164
HBL-100 cells Normal Homo sapiens CVCL_4362
MDA-MB-231 cells Breast adenocarcinoma Homo sapiens CVCL_0062
BT-549 cells Invasive breast carcinoma Homo sapiens CVCL_1092
In Vivo Model
T47D xenografts were established in 5-week-old nude mice (Shanghai SLAC Laboratory Animal Corporation) by inoculating 1 x 107 cells mixed with Matrigel (BD Biosciences) at 1:1 ratio (volume) into the abdominal mammary fat pad. When the tumor reached 50-100 mm3, the mice were assigned randomly into different treatment groups (DMSO, Metformin, SAS, and Metformin + SAS groups). Metformin (200 mg/kg/day) was provided in drinking water. Sulfasalazine was dissolved in dimethyl sulfoxide (DMSO), diluted in PBS, and then intraperitoneally injected into mice at a dose of 250 mg/kg once a day.

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Response regulation Metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc-inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells.
Unspecific Target
In total 3 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Regulator H19 (IncRNA) Suppressor
 Regulator Info 
Pathway Response Glutamate metabolism hsa00250
Autophagy hsa04140
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
Response regulation Metformin and lncRNA-H19 can regulate both autophagy and ferroptosis. Autophagy inducers and H19 can reverse the production of lipid reactive oxygen species and the inhibition of autophagy induced by metformin. Metformin may induce ferroptosis by inhibiting autophagy via H19, and this discovery may facilitate the development of novel therapies for the treatment of breast cancer.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [5]
Responsed Disease Ovarian dysfunction ICD-11: 5A80
 Disease Info 
Responsed Regulator NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vivo Model
n = 6 blank control group was created. The mice in the control group were fed regular food and gavaged with normal saline daily. The mice in the control group were given a high-fat diet and 1 mg/kg of letrozole via gavage for 21 days to establish a PCOS model of insulin resistance and hyperandrogenism. The mice, after successful modeling, were randomly divided into PCOS group and metformin group (n = 6). During the treatment period, the control group continued to be fed with normal feed and given normal saline; the PCOS group was fed with continuous high-fat feed and given letrozole (1 mg/kg/day) by intragastric administration, and the metformin group was given metformin by intragastric administration (200 mg/kg/day). After 30 days of treatment, the experimental mice were euthanized, serum was collected, one mouse ovary was collected for histological examination, and the other was stored in a -80 refrigerator for molecular biology experimental research.

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Response regulation Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. Metformin could regulate ferroptosis to improve polycystic ovary syndrome (PCOS) via the SIRT3/AMPK/mTOR pathway.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [6]
Responsed Disease Degenerative arthritis ICD-11: FA05
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model mKTs (Mouse knee tissues)
In Vivo Model
A total of 50 healthy, wild-type adult male C57BL/6 mice (age, 8weeks; weight 20-25 g) were purchased from the Laboratory Animal Center of Ningxia Medical University. After mice were anesthetized with an intraperitoneal injection of 1% sodium pentobarbital (60 mg/kg), the meniscotibial ligament of the right knee was transected to free the anterior crus of the meniscus, and sham surgery was performed without transecting the meniscotibial ligament. Mice were injected intra-articularly with Erastin (15 mg/kg), and the sham and DMM groups were injected with an equal volume of saline twice a week. Moreover, Met was administered by gavage (200 mg/kg/day). Mice were killed by overdose anesthesia 8 weeks after surgery, and the right knee joint was collected for subsequent experiments.

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Response regulation Metformin alleviates the pathological changes of Osteoarthritis by inhibiting ferroptosis in OA chondrocytes, alleviating subchondral sclerosis and reducing abnormal angiogenesis in subchondral bone in advanced OA.
References
Ref 1 Metformin induces ferroptosis by targeting miR-324-3p/GPX4 axis in breast cancer. Acta Biochim Biophys Sin (Shanghai). 2021 Mar 2;53(3):333-341. doi: 10.1093/abbs/gmaa180.
Ref 2 FAM98A promotes resistance to 5-fluorouracil in colorectal cancer by suppressing ferroptosis. Arch Biochem Biophys. 2022 Jun 15;722:109216. doi: 10.1016/j.abb.2022.109216. Epub 2022 Apr 11.
Ref 3 Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J Exp Clin Cancer Res. 2021 Jun 23;40(1):206. doi: 10.1186/s13046-021-02012-7.
Ref 4 Metformin may induce ferroptosis by inhibiting autophagy via lncRNA H19 in breast cancer. FEBS Open Bio. 2022 Jan;12(1):146-153. doi: 10.1002/2211-5463.13314. Epub 2021 Oct 27.
Ref 5 Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis. Front Endocrinol (Lausanne). 2023 Jan 23;14:1070264. doi: 10.3389/fendo.2023.1070264. eCollection 2023.
Ref 6 Metformin alleviates osteoarthritis in mice by inhibiting chondrocyte ferroptosis and improving subchondral osteosclerosis and angiogenesis. J Orthop Surg Res. 2022 Jun 28;17(1):333. doi: 10.1186/s13018-022-03225-y.