Ferroptosis Target Information

General Information of the Ferroptosis Target (ID: TAR10007)

Target Name	Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12)
Synonyms	Arachidonate (12S)-lipoxygenase ; Arachidonate (15S)-lipoxygenase ; Linoleate (13S)-lipoxygenase; Lipoxin synthase 12-LO; Platelet-type lipoxygenase 12 Click to Show/Hide
Gene Name	ALOX12
Sequence	MGRYRIRVATGAWLFSGSYNRVQLWLVGTRGEAELELQLRPARGEEEEFDHDVAEDLGLL QFVRLRKHHWLVDDAWFCDRITVQGPGACAEVAFPCYRWVQGEDILSLPEGTARLPGDNA LDMFQKHREKELKDRQQIYCWATWKEGLPLTIAADRKDDLPPNMRFHEEKRLDFEWTLKA GALEMALKRVYTLLSSWNCLEDFDQIFWGQKSALAEKVRQCWQDDELFSYQFLNGANPML LRRSTSLPSRLVLPSGMEELQAQLEKELQNGSLFEADFILLDGIPANVIRGEKQYLAAPL VMLKMEPNGKLQPMVIQIQPPNPSSPTPTLFLPSDPPLAWLLAKSWVRNSDFQLHEIQYH LLNTHLVAEVIAVATMRCLPGLHPIFKFLIPHIRYTMEINTRARTQLISDGGIFDKAVST GGGGHVQLLRRAAAQLTYCSLCPPDDLADRGLLGLPGALYAHDALRLWEIIARYVEGIVH LFYQRDDIVKGDPELQAWCREITEVGLCQAQDRGFPVSFQSQSQLCHFLTMCVFTCTAQH AAINQGQLDWYAWVPNAPCTMRMPPPTTKEDVTMATVMGSLPDVRQACLQMAISWHLSRR QPDMVPLGHHKEKYFSGPKPKAVLNQFRTDLEKLEKEITARNEQLDWPYEYLKPSCIENS VTI Click to Show/Hide
Family	Lipoxygenase family
Function	Catalyzes the regio and stereo-specific incorporation of molecular oxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species. Mainly converts arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to the specific bioactive lipid (12S)-hydroperoxyeicosatetraenoate/(12S)-HPETE. Through the production of bioactive lipids like (12S)- HPETE it regulates different biological processes including platelet activation . It can also catalyze the epoxidation of double bonds of polyunsaturated fatty acids such as (14S)-hydroperoxy-docosahexaenoate/(14S)-HPDHA resulting in the formation of (13S,14S)-epoxy-DHA. Furthermore, it may participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro- resolving mediators (SPMs) like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets. An additional function involves a multistep process by which it transforms leukotriene A4/LTA4 into the bioactive lipids lipoxin A4/LXA4 and lipoxin B4/LXB4, both are vasoactive and LXA4 may regulate neutrophil function via occupancy of specific recognition sites. Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to (13S)- hydroperoxyoctadecadienoate/ (13S-HPODE). Due to its role in regulating both the expression of the vascular endothelial growth factor (VEGF, an angiogenic factor involved in the survival and metastasis of solid tumors) and the expression of integrin beta-1 (known to affect tumor cell migration and proliferation), it can be regarded as protumorigenic. Important for cell survival, as it may play a role not only in proliferation but also in the prevention of apoptosis in vascular smooth muscle cells. Click to Show/Hide
Gene ID	239
Uniprot ID	P18054
Target Type	Driver Suppressor Marker
Mechanism Diagram	Click to View the Original Diagram

Tissue Relative Abundances of This Target

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

ALOX12 can be involved in and affect the ferroptosis by the following regulators, and result in corresponding disease/drug response(s). You can browse corresponding disease or drug response(s) resulting from the regulation of certain regulators.

Browse Regulator related Disease

Browse Regulator related Drug

hsa-miR-7-5p (miRNA)

Regulator Info

Cervical cancer [ICD-11: 2C77]

In total 1 item(s) under this disease				Disease Info
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator				[1]
Regulator for Ferroptosis	Suppressor
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HeLa cells	Endocervical adenocarcinoma	Homo sapiens	CVCL_0030
In Vitro Model	SAS cells	Tongue squamous cell carcinoma	Homo sapiens	CVCL_1675
Response Description	Knockdown of miR-7-5p increased reactive oxygen species (ROS), mitochondrial membrane potential, and intracellular Fe2+amount. Furthermore, miR-7-5p knockdown results in the down-regulation of the iron storage gene expression such as ferritin, up-regulation of the ferroptosis marker ALOX12 gene expression, and increases of Liperfluo amount in Endocervical adenocarcinoma.

Dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH)

Regulator Info

Anemia [ICD-11: 3A9Z]

In total 1 item(s) under this disease				Disease Info
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator				[2]
Regulator for Ferroptosis	Suppressor
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	AHH-1 cells	Normal	Homo sapiens	CVCL_3640
In Vivo Model	4-week male C57BL/6J mice (20-22 g) were obtained from the vital river and preconditioned for one week. Mice were divided into two groups, either exposed to benzene or fresh air in the exposure system for 6 h/day, 6 days/week, for two months. In the last exposure day, the mice were fast for 10 h. Subsequently, the mice were injected with tribromoethanol (T48402, Sigma, USA) (300 mg/kg). Click to Show/Hide
Response Description	The iron-regulatory system IRP1, ferroptosis regulator DHODH, and fatty acids metabolism rate-limiting enzyme ALOX12 were the crucial influencers in regulating ferroptosis, this provides the potential target in attenuating benzene-induced anemia of inflammation.

Unspecific Regulator

Pancreatic cancer [ICD-11: 2C10]

In total 1 item(s) under this disease				Disease Info
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator				[3]
Responsed Drug	Dihydroartemisinin		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	Panc02 cells	Pancreatic ductal adenocarcinoma	Mus musculus	CVCL_D627
	PANC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0480
In Vivo Model	Six to eight-week-old female C57BL/6 mice were purchased from the Experimental Animal Center of Military Medical Sciences (Beijing, China). C57BL/6 mice were anesthetized and the tail of the pancreas was exposed. Panc 02 cells were resuspended in PBS at a concentration of 1 x 10⁶ cells/0.1 ml and 50 ul cells were injected into the tail of the pancreas. Tumor-bearing mice were randomly divided into two groups (3 days after implantation). The control group was intraperitoneally injected 200 ul PBS daily for 10 days, and the DHA group was intraperitoneally injected with 100 mg/kg DHA daily for 10 days. The pancreatic tumors and spleens of the mice were collected for subsequent analysis. Click to Show/Hide
Response Description	Dihydroartemisinin has anti-tumor effect in pancreatic cancer cells in vitro and in vivo. DHA treatment induced ferroptosis by increasing P53 and AOLX12 expression.

Parkinson disease [ICD-11: 8A00]

In total 1 item(s) under this disease				Disease Info
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator				[4]
Responsed Drug	Paraquat		Investigative	Drug Info
Pathway Response	Apoptosis			hsa04210
	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell autophagy
	Cell apoptosis
In Vitro Model	SH-SY5Y cells	Neuroblastoma	Homo sapiens	CVCL_0019
In Vivo Model	Twenty male C57BL/6 mice at 12 weeks old were purchased from Hebei Medical University Experimental Animal Center. 10 mice of the experimental group were intraperitoneally injected with PQ (10 mg PQ (salt)/kg/dose) three times a week for 3 weeks according to the previous report. Ten mice of the control group were intraperitoneally injected with the same dose of normal saline. Once the experimental schedule was completed, firstly, the animals were used for behavioral tests. Then, the mice were anesthetized with 0.4% pentobarbital sodium (1 mL/100 g) solution and perfused. The substantia nigra tissue was exfoliated for subsequent experiments. Click to Show/Hide
Response Description	Paraquat (PQ) significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of Parkinson's disease occurrence.

Status epilepticus [ICD-11: 8A66]

In total 1 item(s) under this disease				Disease Info
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator				[5]
Responsed Drug	Baicalein		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	All adult male C57/BL6 mice weighing 18-22g were obtained from the Experimental Animal Center of Central South University, China. Animals were randomly divided into six groups as follows: 1) control group (n = 6) was given vehicle intracranial injection (PBS 5 ul); 2) FeCl3 group (n = 6) was given 5 ul 50 mM FeCl3; 3) and 4) baicalein groups were pretreated with baicalein 50 mg/kg (n = 6) and 100 mg/kg (n = 6) 30 min prior to FeCl3 administration, respectively; 5) ferroptosis inhibitor group (n = 6) was administered continuously with 10 mg/kg Lipo-1 3 d prior to FeCl3 administration; and 6) baicalein administration group (n = 6) was given 100 mg/kg baicalein once by intraperitoneal injection 30 min prior to 5 ul PBS administration. Click to Show/Hide
Response Description	Baicalein, as a naturel bioactive compound, could ameliorate behavioral seizures and play a key neuroprotective role in FeCl3-induced posttraumatic epileptic seizures through inhibiting ferroptosis and its neuroprotection might be related to suppression of 12-LOX/15-LOX.

Health [ICD-11: N.A.]

In total 1 item(s) under this disease				Disease Info
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator				[7]
Responsed Drug	Hydrogen Sulfide		Investigative	Drug Info
Pathway Response	Fatty acid metabolism			hsa01212
Pathway Response	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	C2C12 cells	Normal	Mus musculus	CVCL_0188
Response Description	RSL3 induced ROS generation, inhibited CSE/H2S (Hydrogen sulfide) system, damaged mitochondrial structure, increased acetyl-CoA content and lipid peroxidation, which eventually lead to ferroptosis. Supplement of H2S normalized oxidative stress, acetyl-CoA content and ALOX12 acetylation and then protected myoblasts from RSL3-induced ferroptosis.

Histone-lysine N-methyltransferase 2D (KMT2D)

Regulator Info

Health [ICD-11: N.A.]

In total 1 item(s) under this disease				Disease Info
Experiment 1 Reporting the Ferroptosis-centered Disease Response of This Regulator				[6]
Regulator for Ferroptosis	Driver
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
	Cell proliferation
	Cell differentiation
In Vitro Model	NHEK/SV3 cells	Normal	Homo sapiens	CVCL_9Q50
	3T3-J2 cells	Normal	Mus musculus	CVCL_W667
In Vivo Model	All animal protocols were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania. Mice were maintained on a mixed C57BL/6 background on a standard light-dark cycle. Mice carrying Mll4SET floxed alleles, Mll3SET floxed alleles, or a combination of both of these were crossed with Krt14-Cre transgenic mice. Click to Show/Hide
Response Description	MLL4 (KMT2D) deficiency profoundly alters epidermal gene expression and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Alox12b, and Aloxe3).

Unspecific Regulator

Dihydroartemisinin [Investigative]

In total 1 item(s) under this drug				Drug Info
Experiment 1 Reporting the Ferroptosis-centered Drug Response of This Regulator				[3]
Responsed Disease	Pancreatic cancer [ICD-11: 2C10]			Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell proliferation
In Vitro Model	Panc02 cells	Pancreatic ductal adenocarcinoma	Mus musculus	CVCL_D627
	PANC-1 cells	Pancreatic ductal adenocarcinoma	Homo sapiens	CVCL_0480
In Vivo Model	Six to eight-week-old female C57BL/6 mice were purchased from the Experimental Animal Center of Military Medical Sciences (Beijing, China). C57BL/6 mice were anesthetized and the tail of the pancreas was exposed. Panc 02 cells were resuspended in PBS at a concentration of 1 x 10⁶ cells/0.1 ml and 50 ul cells were injected into the tail of the pancreas. Tumor-bearing mice were randomly divided into two groups (3 days after implantation). The control group was intraperitoneally injected 200 ul PBS daily for 10 days, and the DHA group was intraperitoneally injected with 100 mg/kg DHA daily for 10 days. The pancreatic tumors and spleens of the mice were collected for subsequent analysis. Click to Show/Hide
Response Description	Dihydroartemisinin has anti-tumor effect in pancreatic cancer cells in vitro and in vivo. DHA treatment induced ferroptosis by increasing P53 and AOLX12 expression.

Paraquat [Investigative]

In total 1 item(s) under this drug				Drug Info
Experiment 1 Reporting the Ferroptosis-centered Drug Response of This Regulator				[4]
Responsed Disease	Parkinson disease [ICD-11: 8A00]			Disease Info
Pathway Response	Apoptosis			hsa04210
	Ferroptosis			hsa04216
	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
	Cell autophagy
	Cell apoptosis
In Vitro Model	SH-SY5Y cells	Neuroblastoma	Homo sapiens	CVCL_0019
In Vivo Model	Twenty male C57BL/6 mice at 12 weeks old were purchased from Hebei Medical University Experimental Animal Center. 10 mice of the experimental group were intraperitoneally injected with PQ (10 mg PQ (salt)/kg/dose) three times a week for 3 weeks according to the previous report. Ten mice of the control group were intraperitoneally injected with the same dose of normal saline. Once the experimental schedule was completed, firstly, the animals were used for behavioral tests. Then, the mice were anesthetized with 0.4% pentobarbital sodium (1 mL/100 g) solution and perfused. The substantia nigra tissue was exfoliated for subsequent experiments. Click to Show/Hide
Response Description	Paraquat (PQ) significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of Parkinson's disease occurrence.

Baicalein [Investigative]

In total 1 item(s) under this drug				Drug Info
Experiment 1 Reporting the Ferroptosis-centered Drug Response of This Regulator				[5]
Responsed Disease	Status epilepticus [ICD-11: 8A66]			Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
Cell Process	Cell ferroptosis
In Vitro Model	HT22 cells	Normal	Mus musculus	CVCL_0321
In Vivo Model	All adult male C57/BL6 mice weighing 18-22g were obtained from the Experimental Animal Center of Central South University, China. Animals were randomly divided into six groups as follows: 1) control group (n = 6) was given vehicle intracranial injection (PBS 5 ul); 2) FeCl3 group (n = 6) was given 5 ul 50 mM FeCl3; 3) and 4) baicalein groups were pretreated with baicalein 50 mg/kg (n = 6) and 100 mg/kg (n = 6) 30 min prior to FeCl3 administration, respectively; 5) ferroptosis inhibitor group (n = 6) was administered continuously with 10 mg/kg Lipo-1 3 d prior to FeCl3 administration; and 6) baicalein administration group (n = 6) was given 100 mg/kg baicalein once by intraperitoneal injection 30 min prior to 5 ul PBS administration. Click to Show/Hide
Response Description	Baicalein, as a naturel bioactive compound, could ameliorate behavioral seizures and play a key neuroprotective role in FeCl3-induced posttraumatic epileptic seizures through inhibiting ferroptosis and its neuroprotection might be related to suppression of 12-LOX/15-LOX.

Hydrogen Sulfide [Investigative]

In total 1 item(s) under this drug				Drug Info
Experiment 1 Reporting the Ferroptosis-centered Drug Response of This Regulator				[7]
Responsed Disease	Health [ICD-11: N.A.]			Disease Info
Pathway Response	Fatty acid metabolism			hsa01212
	Ferroptosis			hsa04216
Cell Process	Cell ferroptosis
In Vitro Model	C2C12 cells	Normal	Mus musculus	CVCL_0188
Response Description	RSL3 induced ROS generation, inhibited CSE/H2S (Hydrogen sulfide) system, damaged mitochondrial structure, increased acetyl-CoA content and lipid peroxidation, which eventually lead to ferroptosis. Supplement of H2S normalized oxidative stress, acetyl-CoA content and ALOX12 acetylation and then protected myoblasts from RSL3-induced ferroptosis.

References

Ref 1	MiR-7-5p Is Involved in Ferroptosis Signaling and Radioresistance Thru the Generation of ROS in Radioresistant HeLa and SAS Cell Lines. Int J Mol Sci. 2021 Aug 2;22(15):8300. doi: 10.3390/ijms22158300.
Ref 2	Iron-dependent ferroptosis participated in benzene-induced anemia of inflammation through IRP1-DHODH-ALOX12 axis. Free Radic Biol Med. 2022 Nov 20;193(Pt 1):122-133. doi: 10.1016/j.freeradbiomed.2022.10.273. Epub 2022 Oct 13.
Ref 3	Dihydroartemisinin inhibits the growth of pancreatic cells by inducing ferroptosis and activating antitumor immunity. Eur J Pharmacol. 2022 Jul 5;926:175028. doi: 10.1016/j.ejphar.2022.175028. Epub 2022 May 13.
Ref 4	Ferritinophagy-Mediated Ferroptosis Involved in Paraquat-Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD. Oxid Med Cell Longev. 2021 Jul 26;2021:9961628. doi: 10.1155/2021/9961628. eCollection 2021.
Ref 5	Baicalein Exerts Neuroprotective Effects in FeCl(3)-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis. Front Pharmacol. 2019 Jun 7;10:638. doi: 10.3389/fphar.2019.00638. eCollection 2019.
Ref 6	MLL4 mediates differentiation and tumor suppression through ferroptosis. Sci Adv. 2021 Dec 10;7(50):eabj9141. doi: 10.1126/sciadv.abj9141. Epub 2021 Dec 10.
Ref 7	Hydrogen sulfide guards myoblasts from ferroptosis by inhibiting ALOX12 acetylation. Cell Signal. 2021 Feb;78:109870. doi: 10.1016/j.cellsig.2020.109870. Epub 2020 Dec 5.

Ferroptosis Target Information

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Correspondence

Prof. Shuiping Liu