Table 1 Small molecule compounds.

PERK agonist

CCT020312

BC

Activates PERK/eIF2α/ATF4/CHOP pathway, mediating G1 cell cycle arrest and apoptosis.

Preclinical

[105, 106]

Cardiac glycoside

Oleandrin

BC

Induces ICD via PERK/eIF2α/ATF4/CHOP pathway.

Preclinical

[104]

Quinone derivative

Dihydrotanshinone I

BC

Targets ERp57, inducing ERS and UPR activation, leading to apoptosis.

Preclinical

[162]

Macrolide

I1amycin E

BC

Promotes apoptosis via ERS-CHOP-Bcl-2 pathway.

Preclinical

[163]

Synthetic compound

AMC-04

BC

Activates ATF4-CHOP and DR5 expression, promoting apoptosis.

Preclinical

[164]

Natural phenol

Curcumin

CRC

Stimulates ATF6 expression and nuclear translocation to activate ERS, influencing apoptosis.

Phase I/II (for cancer prevention/therapy)

[111]

Natural compound

Gambogenic acid

CRC

Induces ERS via Aurora A pathway.

Preclinical

[112]

Triterpenoid saponin

α-Hederin

CRC

Disrupts proteostasis by blocking ERAD and autophagic flux, leading to cell death.

Preclinical

[113]

Proteasome inhibitor

Carfilzomib

CRC

Induces UPR via enhanced CHOP expression and ATF6 activity, increasing caspase-3/7-mediated apoptosis.

Approved (for multiple myeloma); Phase II (for CRC)

[114]

Natural compound

Trichodermic acid

CRC

Induces autophagy, attenuating ERS-mediated apoptosis.

Preclinical

[116]

Flavonol

Fisetin

HCC

Increases apoptosis via intracellular Ca²⁺ release, PERK-ATF4-CHOP signaling, and GRP78 exosome induction.

Preclinical

[119]

Natural red pigment

Prodigiosin

HCC

Induces apoptosis via ERS.

Preclinical

[120]

Sesquiterpene lactone

Xanthatin

HCC

Promotes ATF4 activation, inducing ERS-mediated apoptosis.

Preclinical

[122]

Hormone + TKI

Melatonin + Sorafenib

HCC

Low melatonin inhibits autophagy via PERK-ATF4-Beclin1 pathway, increasing sensitivity to sorafenib.

Phase I/II (for combination therapy)

[123]

Chemotherapy + Polysaccharide

5-Fluorouracil + Konjac glucomannan

HCC

Downregulates TLR4, activating PERK/ATF4/CHOP signaling, enhancing apoptosis in 5-FU-resistant HCC cells.

Preclinical (for combination)

[124]

ATPase inhibitor

BMS-303141

HCC

Induces ERS and activates p-eIF2α/ATF4/CHOP axis to promote apoptosis; synergizes with sorafenib.

Preclinical

[125]

Platinum chemotherapeutic

Lobaplatin

HCC

Induces apoptosis and upregulates PERK-eIF2α-ATF4-CHOP pathway, suppressing proliferation.

Approved (in China for various cancers)

[126]

Isothiocyanate

Sulforaphane

GBM

Activates UPR via ATF4-CHOP axis, inducing apoptosis.

Phase I/II (for various cancers)

[131]

Proteasome inhibitor

Marizomib

GBM

Triggers ERS and promotes apoptosis.

Phase III (for GBM)

[132]

Nucleotide analog

Remdesivir

GBM

Enhances ERS and activates PERK-mediated UPR to induce apoptosis.

Approved (for COVID-19); Preclinical (for GBM)

[133]

Artemisinin derivative

Dihydroartemisinin

GBM

Induces mitochondrial/ER-mediated apoptosis and autophagic cell death.

Phase I/II (for various cancers)

[165]

Flavonoid

Icariside II

LC

Enhances cisplatin-induced cell death by promoting ERS signaling in NSCLC cells.

Preclinical

[144]

Artemisinin derivative

Dihydroartemisinin

LC

Triggers ICD via ferroptosis-induced ERS and DNA damage.

Phase I/II (for various cancers)

[145]

Gold complex

L1Au2

LC

Promotes GPX4 degradation, inducing ferroptosis, ERS, and ICD.

Preclinical

[146]

Alkaloid

Narciclasine

LC

Enhances cisplatin-induced apoptosis via UPR-mediated NOXA and MCL1 regulation.

Preclinical

[147]

Alkaloid

Fascaplysin

LC

Induces apoptosis and ferroptosis in vitro, improves anti-PD-1 immunotherapy sensitivity in vivo.

Preclinical

[148]

Selenorganic compound

3,3’-Diselenodipropionic acid

LC

Induces apoptosis via extrinsic/intrinsic pathways and ERS in a p53-independent manner.

Preclinical

[149]

Synthetic compound

PPZ023

LC

Causes cell death via PERK-eIF2α-CHOP axis in NSCLC cells/exosomes.

Preclinical

[150]

GRP78 inhibitor

YUM70

PDAC

Binds and inactivates GRP78, leading to ERS-mediated apoptosis.

Preclinical

[155]

Ester

Secoemestrin C

PDAC

Enhances ERS-triggered apoptosis via ERAD ubiquitination and YAP downregulation.

Preclinical

[157]

Multi-target TKI

Anlotinib

PDAC

Induces apoptosis via ROS accumulation-mediated ERS.

Approved (in China for lung cancer); Phase II (for PDAC)

[158]