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. 2023 Jul 26;9:261. doi: 10.1038/s41420-023-01565-0

Table 1.

Evidence for targeting Nrf2 to ameliorate doxorubicin-induced cardiotoxicity.

Category Compound/protein/MicroRNA In vivo/in vitro Model (animals/cells) Intervention parameters Impact on Nrf2 signaling pathway Reference
Dose Route
Clinical medicines Dimethyl fumarate In vivo DOX-induced SD rats 40, 80 mg/kg, twice a day PO

Nuclear Nrf2, HO-1, NQO1, Bcl-2 expression ↑ ;

Bax expression↓

 [168]
In vitro DOX-induced primary myocytes 10, 20 μM for 4 h N/A
Propofol In vitro DOX-induced H9c2 cells 5, 10, 20 μM for 1 h N/A Nuclear Nrf2, Gpx4 expression↑ [29]
Phytochemicals—flavonoids Quercetin In vivo DOX-induced SD rats 10, 25, 50 mg/kg for 7 weeks PO Nuclear Nrf2 expression↑ [169]
Genistein In vivo DOX-induced 129/sv mice 5 mg/kg for 4 weeks IP

Nuclear Nrf2, HO-1, NQO1 expression ↑ ;

Erk, Bax, Cleaved caspase-3 expression↓

 [170]
Didymin In vivo DOX-induced BALB/c mice 2, 4, 8 mg/kg every day for 1 week IP

Nuclear Nrf2, HO-1, GCLM, p-PI3K, p-AKT, Bcl-2 expression ↑ ;

Bax, Caspase-3/9 expression↓

 [171]
In vitro DOX-induced H9c2 cells 5, 10, 20 µg/ml for 4 h N/A
Cardamonin In vivo DOX-induced C57BL/6J mice 20, 40, 80 mg/kg/day IG

Nuclear Nrf2, HO-1, NQO1, GCLM, Bcl-2 expression ↑ ;

Bax, Cleaved caspase-3 expression↓

 [172]
In vitro HL-1 cells 12.5–100 μM N/A
Baicalein In vivo DOX-induced BALB/c mice 25, 50 mg/kg for 15 days PO

Nuclear Nrf2, HO-1, NQO1 expression ↑ ;

Bax/Bcl-2, Cleaved caspase-3, Cleaved PARP expression↓

 [173]
Isoorientin In vivo DOX-induced ICR mice 7.5, 15, 30 mg/kg for 8 times IP

Nuclear Nrf2, Bcl-2 expression ↑ ;

Cleaved caspase-3 expression↓

 [174]
In vitro DOX-induced H9c2 cells 2.5–320 μg/ml N/A
Pinocembrin In vivo DOX-induced C57BL/6J mice 5 mg/kg IP

Nuclear Nrf2, SIRT3 expression ↑ ;

NLRP3, ASC, Cleaved caspase-1, GSDMD-N, IL-18 expression↓

 [30]
In vitro DOX-induced H9c2 cells 1 μM for 48 h N/A
Acacetin In vivo DOX-induced C57BL/6J mice 15 mg/kg for 2 times/day for 3 days SC

Nuclear Nrf2, HO-1, p-AMPK, p-LKB1, SIRT1 expression ↑ ;

Bax, Cleaved caspase-3 expression↓

 [77]
In vitro DOX-induced H9c2 cells 0.1–3 μM N/A
Fisetin In vivo DOX-induced Wistar rats 20, 40 mg/kg/day IG Nuclear Nrf2, HO-1, Gpx4, FTH, FPN, FTL, SIRT1 expression↑ [148]
In vitro DOX-induced H9c2 cells 40 μM for 24 h N/A
Phytochemicals—polyphenols Punicalagin In vitro DOX-induced H9c2 cells 50, 100, 200 μM for 2 h N/A

Nuclear Nrf2, HO-1 expression ↑ ;

Bax/Bcl-2 expression↓

 [176]
Tert-butylhydroquinone In vivo DOX-induced CD1/ICR mice 25 mg/kg/day for 3 days IP Nuclear Nrf2, HO-1, NQO1 expression↑ [177]
Tanshinone I In vivo DOX-induced C57BL/6J mice 5, 10 mg/kg for 4 weeks PO Nuclear Nrf2, HO-1, NQO1, p-AKT expression↑ [178]
In vitro DOX-induced H9c2 cells 10 μM for 24 h N/A
Resveratrol In vivo DOX-induced C57BL/6J mice 30 mg/kg for 12 weeks (cumulative dose to 210 mg/kg) IP Nuclear Nrf2, HO-1, NQO1, Gpx4, SLC7A11, p62 expression↑ [146]
In vitro DOX-induced H9c2 cells 0.5, 1 μM for 0.5 h N/A
Dillenia pentagyna (Roxb) In vivo DOX-induced Balb/c mice

100 mg/kg for 2 days

OR 200 mg/kg for 5 days

 PO Nuclear Nrf2, HO-1 expression↑ [179]
In vitro DOX-induced H9c2 cells 3.125, 6.25, 12.5, 25, 50 μg/ml for 24 h N/A
Resveratrol In vivo DOX-induced C57BL/6J mice 10 mg/kg/day IP Nuclear Nrf2, HO-1, SIRT1 expression↑ [27]
In vitro DOX-induced H9c2 cells 20 μM N/A
Yellow wine In vivo DOX-induced SD rats 30 mg/kg/day for 4 weeks IP

Nuclear Nrf2 expression ↑ ;

Bax/Bcl-2, Caspase-3 expression↓

 [180]
In vitro DOX-induced H9c2 cells 50 mg/l N/A
Phytochemicals—saponins Dioscin In vivo

DOX-induced C57BL/6J mice

DOX-induced SD rats

0, 20, 40 mg/kg/day for 5 days;

3, 4, 10 mg/kg/day for 7 days

 PO Nuclear Nrf2, HO-1, NQO1, MicroRNA-140-5p expression↑ [182]
In vitro DOX-induced H9c2 cells 0–1000 ng/ml for 24 h N/A
Astragaloside IV In vivo DOX-induced SD rats 10 mg/kg/day for 5 weeks IG

Nuclear Nrf2, Gpx4 expression ↑ ;

NOX2, NOX4, Ptgs2 expression↓

 [142]
Phytochemicals—terpenoids Pritimerin In vivo DOX-induced Wistar rats 0.5, 1 mg/kg IP Nuclear Nrf2, HO-1, NQO1, GCLM expression↑ [165]
Geraniol In vivo DOX-induced SD rats 200 mg/kg/day for 15 days PO Nuclear Nrf2, HO-1 expression↑ [183]
Limonin In vivo DOX-induced SD rats 5, 10 mg/kg for 10 weeks IP

Nuclear Nrf2, HO-1, NQO1, GCLM expression ↑ ;

Bax/Bcl-2, Caspase-3 expression↓

 [184]
In vitro DOX-induced H9c2 cells 1, 5, 25 μM for 48 h N/A
Nerolidol In vivo DOX-induced Wistar rats 50 mg/kg for 5 weeks IG

Nuclear Nrf2, HO-1, p-PI3K, p-AKT, Bcl-2 expression ↑ ;

Bax, Caspase-3/9 expression↓

 [80]
Mokko lactone In vivo DOX-induced Wistar rats 15, 30 mg/kg PO

Nuclear Nrf2, HO-1, Bcl-2 expression ↑ ;

Bax, Caspase-3 expression↓

 [185]
Curdione In vitro DOX-induced H9c2 cells 12.5–150 mM N/A

Nuclear Nrf2, HO-1, Bcl-2 expression ↑ ;

Bax, Caspase-3, p-JNK, p-ERK expression↓

 [186]
Nerolidol In vivo DOX-induced Wistar rats 50 mg/kg for 5 days PO

Nuclear Nrf2, HO-1, Bcl-2 expression ↑ ;

Bax, Caspase-3/9 expression↓

 [187]
Asiatic acid In vivo DOX-induced Wistar rats 5, 10, 20 mg/kg for 7 days PO Nuclear Nrf2 expression↑ [188]
Phytochemicals—alkaloids Tetrandrine In vivo DOX-induced C57BL/6J mice 50 mg/kg for 4 days N/A

Nuclear Nrf2 expression ↑ ;

Bax, Cleaved caspase-3 expression↓

 [189]
In vitro DOX-induced NRCM cells N/A
Rutaecarpine In vivo DOX-induced C57BL/6J mice 20 mg/kg for 4 weeks N/A

Nuclear Nrf2, HO-1, p-AKT, GCLM expression ↑ ;

Cleaved caspase-3 expression↓

 [120]
Phytochemicals— sulfur-containing compounds Sulforaphane In vivo DOX-induced 129/sv mice 4 mg/kg for 5 days/week N/A

Nuclear Nrf2, HO-1 expression ↑ ;

Caspase-3 expression↓

 [190]
In vitro DOX-induced H9c2 cells 2.5 μM for 12–14 h N/A
Sulforaphane In vitro DOX-induced H9c2 cells N/A N/A

Nuclear Nrf2, HO-1 expression ↑ ;

Bax, expression↓

 [191]
Synthetic proteins Orosomucoid 1 In vitro DOX-induced H9c2 cells 10, 30, 50, 100 mol N/A

Nuclear Nrf2, HO-1 expression ↑ ;

Cleaved caspase-3 expression↓

 [192]
Follistatin-like 1 In vitro DOX-induced NRCM cells 5 μg/ml N/A

Nuclear Nrf2, Bcl-2 expression ↑ ;

Bax, Caspase-3 expression↓

 [193]
Obestatin In vivo DOX-induced SD rats 100 mg/kg/day for 4 weeks IP

Nuclear Nrf2, Mhrt expression ↑ ;

Caspase-3 expression↓

 [128]
Klotho In vivo DOX-induced SD rats 0.01 mg/kg for twice IP Nuclear Nrf2, HO-1, Prx1 expression↑ [125]
In vitro DOX-induced primary myocytes 400 pmol/l N/A
Fibroblast growth factor-2 In vitro DOX-induced ventricular cardiomyocytes 10 ng/ml for 30 min N/A

Nuclear Nrf2, HO-1, p62/SQSTM1 expression ↑ ;

Cleaved caspase-3, Bnip-3, p53 expression↓

 [28]
Fibroblast growth factor-21 In vivo DOX-induced 129S1/SvImJ mice 100 μg/kg IP Nuclear Nrf2, HO-1, NQO1, CAT expression ↑ ; Caspase-9, Bax/Bcl-2 expression↓ [79]
In vitro DOX-induced H9c2 cells 50 ng/ml for 2 h N/A
Kininogen-1 In vitro DOX-induced H9c2 cells NA N/A Nuclear Nrf2, HO-1 expression↑ [194]
Octreotide In vivo DOX-induced SD rats 20 µg/kg IP Nuclear Nrf2 expression↑ [195]
Inhibitors and activators ADP355 In vivo DOX-induced C57BL/6J mice 200 ml/day for 4 weeks IP Nuclear Nrf2, HO-1, NQO1 expression ↑ ; Bax/Bcl-2 expression↓ [14]
In vitro DOX-induced H9c2 cells N/A N/A
Cilostazol In vivo DOX-induced ICR mice 50 mg/kg for 5 days/week for 6 weeks IP Nuclear Nrf2, HO-1, NQO1 expression↑ [196]
Dapagliflozin In vivo DOX-induced SD rats 0.1 mg/kg for 5 days/week for 5 weeks PO

Nuclear Nrf2, HO-1, NQO1, PI3K, AKT expression ↑ ;

Bax/Bcl-2, NF-κB, IL-8 expression↓

 [31]
Rosiglitazone In vivo DOX-induced Wistar rats 10 mg/kg for 21 days IG Nuclear Nrf2, HO-1, NQO1, Bcl-2 expression↑ [197]
MicroRNAs MicroRNA-200a In vitro DOX-induced H9c2 cells 50nmol/l N/A

Nuclear Nrf2, HO-1 expression ↑ ;

Bax expression↓

 [200]
MicroRNA -152 In vitro DOX-induced NRCM cells 50nmol/l for 48 h N/A Nuclear Nrf2, HO-1, NQO1 expression↑ [201]
MicroRNA-140-5p In vivo DOX-induced C57BL/6J mice 5nmol/g/day for 4 days N/A Nuclear Nrf2, HO-1, NQO1 expression↑ [198]
Other compounds β-LAPachone In vivo DOX-induced C57BL/6J mice 2.5, 5 mg/kg for 3 days IG Nuclear Nrf2, HO-1, SIRT1, p-AMPK, p-LKB1 expression↑ [78]
Naringenin-7-O-glucoside In vitro DOX-induced H9c2 cells 10, 20, 40 μM for 24 h N/A Nuclear Nrf2, HO-1, NQO1, GCLM expression↑ [84]
Chitosan oligosaccharides In vivo DOX-induced SD rats 10, 30, 50, 70, 100 mg/kg for 2 weeks IG

Nuclear Nrf2, HO-1, NQO1, Bcl-2 expression ↑ ;

p-JNK, p-ERK Caspase-3, Caspase-9, Bax expression↓

 [54]
In vitro DOX-induced H9c2 cells 100 μg/ml N/A
Resolvin D1 In vivo DOX-induced C57BL/6J mice 5.30 μg/kg for 1 min IP

Nuclear Nrf2, HO-1, NQO1, Bcl-2 expression ↑ ;

Caspase-3, Caspase-9, Bax expression↓

 [202]
Choline In vivo DOX-induced SD rats 7 mg/kg/day IP Nuclear Nrf2, HO-1, Bcl-2 expression ↑ ; Caspase-3, Bax expression↓ [203]
α-Linolenic acid In vivo DOX-induced SD rats 500 mg/kg IG Nuclear Nrf2, Bcl-2 expression ↑ ; Caspase-3, Bax expression↓ [204]
Tanshinone IIA In vivo DOX-induced mice 15, 30 mg/kg IP Nuclear Nrf2, HO-1, NQO1 expression↑ [76]
In vitro DOX-induced H9c2 cells 1, 3, 5, 10 μM N/A
Danshensu In vivo DOX-induced KM mice 45 mg/kg/day for 3 days IP

Nuclear Nrf2, HO-1, NQO1, Bcl-2 expression ↑ ;

Caspase-3, Bax expression↓

 [205]
Hemin In vivo DOX-induced Wistar rats 2.5, 5, 10 mg/kg for 7 days IP Nuclear Nrf2, HO-1 expression ↑ ; [206]
Shengmai In vivo DOX-induced SD rats 2.7, 5.4, 10.8 ml/kg for 7 days IP Nuclear Nrf2, HO-1, Bcl-2 expression ↑ ; Caspase-3/9, Bax expression↓ [207]
In vitro DOX-induced H9c2 cells 2 ml for 24 h N/A
Dimethyl itaconate In vivo DOX-induced C57BL/6J mice 100 mg/kg for 4 days IP Nuclear Nrf2, HO-1 expression↑ [208]
Ganoderma lucidum polysaccharides In vivo DOX-induced C57BL/6J mice 50, 100 mg/kg PO

Nuclear Nrf2, HO-1, Bcl-2 expression ↑ ;

Bax expression↓

 [209]
In vitro DOX-induced H9c2 cells N/A N/A
Selenium In vivo DOX-induced C57BL/6J mice 0.2 mg/kg for 2 weeks PO

Nuclear Nrf2 expression ↑ ;

NLRP3 expression↓

 [59]

DOX doxorubicin, PO per os, IP intraperitoneal injection, IG intragastrical administration, SC subcutaneous injection, N/A not applicable.