Table 2 Summary of the protective effects against DM by HO-1.

Hemin

HO-1/Nrf2/GPx4

Ferroptosis, oxidative stress

Contrast-induced nephropathy

HK-2 cells, SD rats

[171]

Mesenchymal stem cells-derived exosomes

Nrf2/HO-1

Ferroptosis, inflammation, vascular endothelial cells dysfunction

Diabetes with sepsis

HPME cells, HBMS cells

[167]

Ferrostatin-1

Nrf2/HO-1

Ferroptosis

Diabetes-induced liver injury

C57BL/6 mice

[172]

Liraglutide

Nrf2/HO-1/GPx4

Ferroptosis, fibrosis

Diabetes-induced liver injury

HepG2 cells, C57BL/KsJ mice

[168]

Tetramethylpyrazine

SIRT1/Nrf2/ HO-1

Mitochondrial dysfunction and oxidative stress

Diabetic Alzheimer

C57BL/6 mice

[165]

Albiflorin

Nrf2/HO-1/HMGB1/NF-kB

Inflammation, oxidative stress

Diabetic Alzheimer

SD rats

[166]

Soluble epoxide hydrolase

AMPK/HO-1

Oxidative stress

Diabetic blood-brain barrier dysfunction

C57BL/KsJ

[173]

Salidroside

AKT/Nrf2/HO-1

Apoptosis, fibrosis, hypertrophy

Diabetic cardiomyopathy

H9C2cells, C57BL/KsJ mice

[109]

Myricetin

Nrf2/HO-1, IκB-α/NF-κB/p65, TGFβ/Smad3

Inflammation, oxidative stress Inflammation, apoptosis Fibrosis

Diabetic cardiomyopathy

NRCM cells, DCM mice

[110]

6-Gingerol

Nrf2/HO-1

Ferroptosis, inflammation

Diabetic cardiomyopathy

H9C2 cells, C57BL/6 mice

[174]

Curcumin

AKT/Nrf2/ARE

Oxidative stress, pyroptosis

Myocardial cells, SD rats

[73]

Nrf2/HO-1/GPx4

Ferroptosis

Diabetic cardiomyopathy

Rat H9C2 cells, New Zealand rabbits

[111]

Nrf2/HO-1

Apoptosis, oxidative stress

H9C2 cells, SD rats

[112]

Sargassum wightii fucoidan

Nrf2/HO-1

Apoptosis, fibrosis, oxidative stress

Diabetic cardiomyopathy

Wistar rats

[175]

Polyherbal formulation

NF-kB/Nrf2/HO-1

Inflammation, oxidative stress

Diabetic cardiomyopathy

Wistar rats

[176]

Piceatannol

Nrf2/HO-1, NF-κB

Apoptosis, fibrosis, inflammation, oxidative stress

Diabetic cardiomyopathy

H9C2 cells, SD rats

[177]

Jasminum sambac phenolics extracted

Nrf2/HO-1

Apoptosis, oxidative stress

Diabetic cardiomyopathy

Wistar albino rats

[178]

Fibroblast growth factor-19

AMPK/Nrf2/HO-1

Oxidative stress

Diabetic cardiomyopathy

Cardiomyocytes, C57BL/6 mice

[179]

Quercetin

Nrf2/HO-1

Apoptosis, fibrosis, pyroptosis

Diabetic cardiomyopathy

H9C2 cells, SD rats

[180]

Sinomenine

EGF/Nrf2/HO-1 via microbiota-gut-brain axis

Ferroptosis

Diabetic cognitive dysfunction

HT-22 cells, SD rats

[181]

Artemisinin

Nrf2/HO-1/GPx4

Ferroptosis

Diabetic cognitive dysfunction

C57BL/6J mice

[182]

Hydrogen sulfide

Nrf2/HO-1/NLRP3

Inflammation, oxidative stress

Diabetic cognitive dysfunction

SD rats

[183]

Soy isoflavones

Nrf2/HO-1

Oxidative stress

Diabetic cognitive dysfunction

GK & Wistar rats

[162]

Apocynin

Nrf2/HO-1

Apoptosis, inflammation, oxidative stress

Diabetic cognitive dysfunction

SD rats

[184]

Betulin

HO-1/Nrf-2/NF-κB

Inflammation, oxidative stress

Diabetic cognitive dysfunction

SD rats

[185]

Sirtuin 1

Nrf2-NF-κB

Inflammation, oxidative stress

Diabetic cognitive dysfunction

SD rats

[163]

JQ-1

Nox4-Nrf2

Apoptosis, inflammation, oxidative stress

Diabetic cognitive dysfunction

PC12 cells, Wistar rats

[164]

Quercetin

KEAP1/Nrf2/HO-1

Ferroptosis

Diabetic encephalopathy

PC12 cells, Goto-Kakizak rats

[170]

Bilirubin

Nrf2/HO-1

Ferroptosis, oxidative stress

Diabetic islet transplantation

BALB/c mice

[170]

Notoginsenoside R1

Nrf2/HO-1/TGF-β

Apoptosis, fibrosis; oxidative stress

Diabetic kidney

HK-2 cells, C57BL/6J mice

[146]

–

ATF4/HO-1

Autophagy, apoptosis

Diabetic kidney

MPC5 cells, C57BL/KsJ mice

[186]

Ferrostatin-1

HIF-1α/HO-1

Ferroptosis

Diabetic kidney

C57BLKs/J mice

[78]

Umbelliferone

Nrf2/HO-1

Ferroptosis

Diabetic kidney

HK-2 cells, C57BL/KsJ mice

[156]

Quercetin

Nrf2/HO-1

Ferroptosis

Diabetic kidney

HK-2 cells, C57BL/KsJ mice

[77]

HMGB1

TLR4/NF-κB/HO-1

Ferroptosis

Diabetic kidney

SV40-MES 13 cells, human serum

[157]

Vitamin D receptor

Nrf2/HO-1

Ferroptosis

Diabetic kidney

HK-2 cells, C57BL/KsJ mice

[82]

Oligo-fucoidan

Nrf2/HO-1

Fibrosis

Diabetic kidney

NRK-52E cells, C57BL/6 mice

[151]

Astaxanthin

Nrf2/ARE

Fibrosis

Diabetic kidney

GMCs cells, SD rats

[149]

KC7F2/hemin

HIF-1α/HO-1

Apoptosis, mitochondrial fragmentation, oxidative stress

Diabetic kidney

HK-2 cells, PEPCK Cre mice

[187]

Baicalin

Nrf2/MAPK

Inflammation, oxidative stress

Diabetic kidney

C57BLKs/J mice

[145]

Telmisartan

Nrf2/HO-1

Apoptosis, angiogenesis, inflammation, oxidative stress

Diabetic kidney

SD rats

[153]

Dapagliflozin

miR-155-5p/HO-1/NLRP3

Pyroptosis

Diabetic kidney

MPC5 cells, C57BL/6 mice

[69]

Syringaresinol

NLRP3/Caspase-1/GSDMD

Pyroptosis

Diabetic kidney

RTE cells, C57BL/6J mice

[72]

Atorvastatin

MALAT1/miR-200c/ Nrf2

Pyroptosis

Diabetic kidney

MPC5 cells

[70]

Triptolide

Nrf2/HO-1/NLRP3

Pyroptosis, oxidative stress

Diabetic kidney

MPC5 cells, C57BL/6J mice

[71]

Shenkang

Keap1/Nrf2/HO-1

Oxidative stress

Diabetic kidney

HK-2 cells, SD rats

[10]

Echinochrome A

AMPKα/Nrf2/HO-1

Fibrosis, mitochondrial function, oxidative stress

Diabetic kidney

C57BL/KsJ mice

[147]

Sinapic acid

Nrf-2/HO-1 Nrf-2/HO-1, NF-kB

Apoptosis, inflammation, oxidative stress

Diabetic kidney Diabetic cardiomyopathy

Wistar rats

[154] [188]

Shenkang Pills

HIF-1α/HO-1

Ferroptosis

Diabetic kidney

C57BL/6 mice

[189]

Fish oil

Nrf2/ARE

Inflammation, oxidative stress

Diabetic cognitive dysfunction

SD rats

[190]

Melatonin

Nrf2/HO-1

Ferroptosis

Diabetic osteoporosis

MC3T3-E1 cells, SD rats

[191]

Maresin-1

Nrf2/HO-1/GPx4

Ferroptosis

Diabetic retinopathy

ARPE-19 cells, C57BL/6 mice

[192]

Amygdalin

Nrf2/ARE

Ferroptosis, oxidative stress

Diabetic retinopathy

HRE cells, SD rats

[161]

n-butylidenephthalide

Nrf2/HO-1

Apoptosis, senescence, tight junction impairment of retinal pigment epithelium

Diabetic retinopathy

ARPE-19 cells, C57BL/6 mice

[193]

Urolithin A

Nrf2/HO-1

Inflammation, oxidative stress

Diabetic retinopathy

HRE cells, SD rats

[194]

Arjunolic acid

AMPK/mTOR/HO-1

Apoptosis, autophagy, inflammation

Diabetic retinopathy

ARPE-19 cells, SD rats

[195]

Hydroxysafflor yellow A

Nrf2/HO-1

Apoptosis

Diabetic retinopathy

Wistar rats

[160]

Platycodin D

TLR4/MyD88/NF-κB Nrf2/HO-1

Inflammation, oxidative stress

Diabetic retinopathy

ARPE-19 cells, SD rats

[196]

Astaxanthin

Nrf2/keap1

Apoptosis, inflammation, oxidative stress

Diabetic retinopathy

SD rats

[197]

Tricin

Sestrin2/Nrf2

Oxidative stress and angiogenesis

Diabetic retinopathy

ARPE-19 cells, SD rats

[198]

Carnosol

ERK/Nrf2/HO-1

Apoptosis, oxidative stress

Diabetic retinopathy

HRE cells

[199]

Rhaponticin

Nrf2/HO-1/NF-κB

Inflammation, oxidative stress

Diabetic retinopathy

Wistar rats

[200]

Nicotinamide mononucleotide

SIRT1/Nrf2/HO-1

Apoptosis, cell migration, and junctions

Diabetic retinopathy

HCECs cells

[201]

sp²-Iminosugar Glycolipid Sulfoxide

HO-1/IL-10

Inflammation, M1→M2

Diabetic Retinopathy

Bv.2 cells, Bio-Breeding rats

[159]

MG132

Nrf2/ARE

Oxidative stress, 26s proteasome activity

Diabetic Retinopathy

HCECs cells, SD rats

[202]

Acteoside

Keap1/Nrf2/ARE

Apoptosis, oxidative stress

Diabetic Retinopathy

ARPE-19 cells, C57BL/6 mice

[203]

Scoparia dulcis L. extract

Nrf2/HO-1

Inflammation, oxidative stress

Diabetic Retinopathy

ARPE-19 cells

[204]

Diosgenin

AMPK/Nrf2/HO-1

Inflammation, oxidative stress

Diabetic Retinopathy

ARPE‐19 cells

[205]

Acidic polysaccharides

Nrf2/ARE

Oxidative stress, inhibit angiogenesis

Diabetic Retinopathy

HUVECs cells, C57BL/KsJ mice

[206]

Gynura divaricata (L.) DC.

Nrf2/HO-1

Apoptosis, angiogenesis, oxidative stress

Diabetic wound healing

HUVECs cells, SD rats

[133]

Thermosensitive Hydrogel Incorporating Prussian Blue Nanoparticles

Nrf2/HO-1

Inflammation, oxidative stress

Diabetic wound healing

HUVECs cells, C57BL/6J mice

[207]

gallocatechin (GC)/silver nanoparticles

Nrf2/HO-1

Inflammation, oxidative stress

Diabetic wound healing

SD rats

[208]

San Huang Xiao Yan

AMPK/Nrf2/HMGB1

Inflammation, oxidative stress

Diabetic wound healing

RAW264.7 cells, SD rats

[209]

Circulating exosomal miR-181b-5p

Nrf2/HO-1

Angiogenesis, cells senescence

Diabetic wound healing

HUVECs cells, C57BL/6J mice

[210]

Tetrahedral framework nucleic acids

Akt/Nrf2/HO-1

Inflammation, oxidative stress

Diabetic wound healing

HUVECs cells, Wistar rats

[211]

Liraglutide

HIF-1α/HO-1

Apoptosis, oxidative stress

Diabetic wound healing

HUVECs cells, C57BL/KsJ mice

[134]

Berberine-modified ZnO nano-colloids hydrogel

Nrf2/HO-1/NQO1

Oxidative stress

Diabetic wound healing

HaCaT cells, NIH-3T3 cells, SD rats

[212]

Polygonatum kingianum

Nrf2/HO-1

Inflammation, oxidative stress

Diabetic wound healing

SD rats

[213]

sodium bisulfide

HO-1/TNF-α

Inflammation, oxidative stress

Diabetic wound healing

SD rats

[214]

dimethyl fumarate

Nrf2/HO-1

Inflammation, oxidative stress

Diabetic wound healing

Macrophages, Wistar rats

[215]

Turmeric-derived nanoparticles functionalized aerogel

Nrf2/HO-1

Apoptosis, macrophage polarization, oxidative stress

Diabetic wound healing

L929 cells, RAW264.7 cells, C57BL/6J mice

[40]