General Information of the Ferroptosis Regulator (ID: REG10404)
Regulator Name Mothers against decapentaplegic homolog 3 (SMAD3)
Synonyms
MADH3; JV15-2; SMAD family member 3
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Gene Name SMAD3
Gene ID 4088
Regulator Type Protein coding
Uniprot ID P84022
Sequence
MSSILPFTPPIVKRLLGWKKGEQNGQEEKWCEKAVKSLVKKLKKTGQLDELEKAITTQNV
NTKCITIPRSLDGRLQVSHRKGLPHVIYCRLWRWPDLHSHHELRAMELCEFAFNMKKDEV
CVNPYHYQRVETPVLPPVLVPRHTEIPAEFPPLDDYSHSIPENTNFPAGIEPQSNIPETP
PPGYLSEDGETSDHQMNHSMDAGSPNLSPNPMSPAHNNLDLQPVTYCEPAFWCSISYYEL
NQRVGETFHASQPSMTVDGFTDPSNSERFCLGLLSNVNRNAAVELTRRHIGRGVRLYYIG
GEVFAECLSDSAIFVQSPNCNQRYGWHPATVCKIPPGCNLKIFNNQEFAALLAQSVNQGF
EAVYQLTRMCTIRMSFVKGWGAEYRRQTVTSTPCWIELHLNGPLQWLDKVLTQMGSPSIR
CSSVS

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Family Dwarfin/SMAD family
Function
Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP- 1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. { | , | , | , | , | , | , | , | , | , | , | }.

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HGNC ID
HGNC:6769
KEGG ID hsa:4088
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
SMAD3 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).
Browse Target
Browse Disease
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NADPH oxidase 4 (NOX4) [Driver]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Driver
Responsed Disease Unilateral ureteral obstruction ICD-11: MG30
Responsed Drug Tectorigenin Investigative
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
mRTECs (Mouse renal tubular epithelial cells)
In Vivo Model
The male C57BL/6 mice (8 weeks old, 22-25 g body weight) used in this study were purchased from Dashuo Bio-Technique Co. Ltd. (Chengdu, China) and were maintained in 12 hr of light/12 hr of darkness. The mice were randomly divided into the following 4 groups (n = 8 per group): Sham, UUO, UUO with tectorigenin (20 mg/kg/day, dissolved in saline with 10% dimethyl sulfoxide [DMSO]) or irbesartan (IRB, a positive control, 20 mg/kg/day) treatment. After anesthesia with 1% pentobarbital, the left ureter was exposed through the lower left incision on the midline of the back and blocked by two-point ligation with 40 silk thread as previously described. The Sham-operated mice underwent the same operation but absence of ligation. The tectorigenin and IRB group were administered intraperitoneally with drug daily for 7 consecutive days since surgery. Sham-operated mice and UUO mice were received the equal volume of solvent.

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Response regulation Tectorigenin exerts as a Smad3 inhibitor to suppress Smad3 activation through an Nox4-dependent mechanism. Tectorigenin protects against unilateral ureteral obstruction by inhibiting Smad3-mediated ferroptosis and fibrosis.
Cystine/glutamate transporter (SLC7A11) [Driver; Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Chronic kidney disease ICD-11: GB61
Responsed Drug Formononetin Investigative
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
mPRTECs (Mouse primary renal tubular epithelial cells)
In Vivo Model
For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium(30 mg/kg). Then, UUO surgery orsham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10% DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10% DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium (30 mg/kg). Then, UUO surgery or sham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10 % DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10 % DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO.

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Response regulation Formononetin (FN) alleviates chronic kidney disease (CKD) by impeding ferroptosis-associated fibrosis by suppressing the Smad3/ATF3/SLC7A11 signaling and could serve as a candidate therapeutic drug for CKD. In addition, FN also promoted the separation of the Nrf2/Keap1 complex and enhanced Nrf2 nuclear accumulation.
Chronic kidney disease [ICD-11: GB61]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Mothers against decapentaplegic homolog 3 (SMAD3) Protein coding
Responsed Drug Formononetin Investigative
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
mPRTECs (Mouse primary renal tubular epithelial cells)
In Vivo Model
For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium(30 mg/kg). Then, UUO surgery orsham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10% DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10% DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium (30 mg/kg). Then, UUO surgery or sham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10 % DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10 % DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO.

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Response regulation Formononetin (FN) alleviates chronic kidney disease (CKD) by impeding ferroptosis-associated fibrosis by suppressing the Smad3/ATF3/SLC7A11 signaling and could serve as a candidate therapeutic drug for CKD. In addition, FN also promoted the separation of the Nrf2/Keap1 complex and enhanced Nrf2 nuclear accumulation.
Unilateral ureteral obstruction [ICD-11: MG30]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Mothers against decapentaplegic homolog 3 (SMAD3) Protein coding
Responsed Drug Tectorigenin Investigative
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
mRTECs (Mouse renal tubular epithelial cells)
In Vivo Model
The male C57BL/6 mice (8 weeks old, 22-25 g body weight) used in this study were purchased from Dashuo Bio-Technique Co. Ltd. (Chengdu, China) and were maintained in 12 hr of light/12 hr of darkness. The mice were randomly divided into the following 4 groups (n = 8 per group): Sham, UUO, UUO with tectorigenin (20 mg/kg/day, dissolved in saline with 10% dimethyl sulfoxide [DMSO]) or irbesartan (IRB, a positive control, 20 mg/kg/day) treatment. After anesthesia with 1% pentobarbital, the left ureter was exposed through the lower left incision on the midline of the back and blocked by two-point ligation with 40 silk thread as previously described. The Sham-operated mice underwent the same operation but absence of ligation. The tectorigenin and IRB group were administered intraperitoneally with drug daily for 7 consecutive days since surgery. Sham-operated mice and UUO mice were received the equal volume of solvent.

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Response regulation Tectorigenin exerts as a Smad3 inhibitor to suppress Smad3 activation through an Nox4-dependent mechanism. Tectorigenin protects against unilateral ureteral obstruction by inhibiting Smad3-mediated ferroptosis and fibrosis.
Formononetin [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [2]
Drug for Ferroptosis Suppressor
Response Target Cystine/glutamate transporter (SLC7A11) Driver; Suppressor
Responsed Disease Chronic kidney disease ICD-11: GB61
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
mPRTECs (Mouse primary renal tubular epithelial cells)
In Vivo Model
For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium(30 mg/kg). Then, UUO surgery orsham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10% DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10% DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO. For UUO-induced CKD, the mice were randomly assigned into four groups (n = 6 per group): UUO, UUO + FN, UUO + VST, and Sham. The mice were anesthetized by intraperitoneal injection of pentobarbital sodium (30 mg/kg). Then, UUO surgery or sham operation was performed as previously described. Mice in the UUO + FN group were orally administrated with 40 mg/kg/day FN (dissolved in 10 % DMSO). For positive control, mice in UUO + VST group were orally treated with 20 mg/kg/day VST (dissolved in 10 % DMSO). Mice in the UUO and Sham groups were given equivalent solvent by oral. All mice were sacrificed 7 days post-UUO.

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Response regulation Formononetin (FN) alleviates chronic kidney disease (CKD) by impeding ferroptosis-associated fibrosis by suppressing the Smad3/ATF3/SLC7A11 signaling and could serve as a candidate therapeutic drug for CKD. In addition, FN also promoted the separation of the Nrf2/Keap1 complex and enhanced Nrf2 nuclear accumulation.
Tectorigenin [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Suppressor
Response Target NADPH oxidase 4 (NOX4) Driver
Responsed Disease Unilateral ureteral obstruction ICD-11: MG30
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
mRTECs (Mouse renal tubular epithelial cells)
In Vivo Model
The male C57BL/6 mice (8 weeks old, 22-25 g body weight) used in this study were purchased from Dashuo Bio-Technique Co. Ltd. (Chengdu, China) and were maintained in 12 hr of light/12 hr of darkness. The mice were randomly divided into the following 4 groups (n = 8 per group): Sham, UUO, UUO with tectorigenin (20 mg/kg/day, dissolved in saline with 10% dimethyl sulfoxide [DMSO]) or irbesartan (IRB, a positive control, 20 mg/kg/day) treatment. After anesthesia with 1% pentobarbital, the left ureter was exposed through the lower left incision on the midline of the back and blocked by two-point ligation with 40 silk thread as previously described. The Sham-operated mice underwent the same operation but absence of ligation. The tectorigenin and IRB group were administered intraperitoneally with drug daily for 7 consecutive days since surgery. Sham-operated mice and UUO mice were received the equal volume of solvent.

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Response regulation Tectorigenin exerts as a Smad3 inhibitor to suppress Smad3 activation through an Nox4-dependent mechanism. Tectorigenin protects against unilateral ureteral obstruction by inhibiting Smad3-mediated ferroptosis and fibrosis.
References
Ref 1 Tectorigenin protects against unilateral ureteral obstruction by inhibiting Smad3-mediated ferroptosis and fibrosis. Phytother Res. 2022 Jan;36(1):475-487. doi: 10.1002/ptr.7353. Epub 2021 Dec 29.
Ref 2 Formononetin ameliorates ferroptosis-associated fibrosis in renal tubular epithelial cells and in mice with chronic kidney disease by suppressing the Smad3/ATF3/SLC7A11 signaling. Life Sci. 2023 Feb 15;315:121331. doi: 10.1016/j.lfs.2022.121331. Epub 2022 Dec 29.