Table 1 The UPR regulators in CRC and their functions, targeting drugs, biomarkers and literatures

ARE

•Counteract the harmful effects of reactive oxidants

•Restore redox balance

[99, 100]

ASK1

Regulate apoptosis signal

[11, 12]

ATF4

Regulating the expression of genes involved in redox balance, amino acid metabolism, protein folding, autophagy and cell survival

CFZ&ACY-1215

[15, 16]

ATF6

Induce ER biogenesis, chaperone up-regulation and unfolded/misfolded proteins degradation

A biomarker to distinguish LGD from inflammatory regenerative epithelium in UC patients

[38, 115, 119]

CHOP

Induce apoptosis

•Fucoidan

•Small-molecule inhibitor 42,215

•2-(3,4-dihydroxyphenyl) ethanol (DPE)

•Brefeldin A (BFA)

•Resveratrol

•Piperine

•Curcumin

•CFZ&ACY-1215

[17, 120,121,122,123,124,125,126]

EIF2ɑ

Translation initiation

•Fucoidan

•Small-molecule inhibitor 42,215

•2-(3,4-dihydroxyphenyl) ethanol (DPE)

•Resveratrol

•CFZ&ACY-1215

[120,121,122, 124]

FOXO

Suppress tumour by promoting cell cycle arrest and apoptosis and preventing the accumulation of damages induced by genotoxic agents and oxidative stress

[102,103,104]

GRP78

•Involves in proper protein folding and proteasome degradation of unfolded/misfolded protein

•ER Ca2 + binding

•Orchestrates the activation of transmembrane ER stress sensors

•Berberine (BBR)

•Mung bean trypsin inhibitor (mTI)

•Paclitaxel

(-)-•Epigallocatechin gallate (EGCG)

•A biomarker for prognosis and early diagnosis of CRC

•A biomarker for response of CRC patients to DNA-targeting agents

•A biomarker determines response to fluoropyrimidine-based adjuvant chemotherapy

[68, 79,80,81,82,83, 86, 87]

IRE1ɑ

•Induce ERAD to facilitate cell survival

•Interact with JNK, resulting in cell apoptosis

•Promote angiogenesis

•Fucoidan

•2-(3,4-dihydroxyphenyl) ethanol (DPE)

•CFZ&ACY-1215

[46, 92, 93, 120, 121]

JNK

Induce apoptosis

•2-(3,4-dihydroxyphenyl) ethanol (DPE)

•Piperine

•Curcumin

•CFZ&ACY-1215

[11, 121, 125, 126]

KEAP1

•Counteract the harmful effects of reactive oxidants

•Restore redox balance

[99, 100]

MKK4

Hinder metastasis

[65,66,67]

NRF2

Increasing genes involved in antioxidation

[17]

PERK

Is central in the switch between the adaptation and apoptosis

•Small-molecule inhibitor 42,215

•2-(3,4-dihydroxyphenyl) ethanol (DPE)

[16, 17, 121, 122]

ROS

Increase cell death

Piperine

[19, 125]

s/TAP73

Promoting CRC cell proliferation and colony formation

[97]

TRAF2

Interact with tumor necrosis factor receptor and many other signaling molecules

[11, 12, 92]

VEGFA

Stimulate angiogenesis

[59, 96]

VEGFR2

Stimulate angiogenesis

[59, 96]

XBP1

Mediated stemness, proliferation and metastasis

Fucoidan

A biomarker in CRC invasion and metastasis

[35, 37, 41, 89, 95, 96, 120]