Table. 2.

Bioactive compounds that trigger ER stress-dependent apoptosis in liver cancer

Compound	Description	Mechanisms of Action	Ref
Annona muricata L. ethanol extract	Plant that contains chemical agents for cancer treatment	Induces ER-stressed apoptosis via enhanced BiP, PERK, HSP90B1, DPYSL5, eIF2α, and CHOP in HepG2 cells	(111)
Bacitracin	Cyclic polypeptide antibiotic	Inhibits P4HB, inducing ER stress and apoptosis in HCC in vivo. Boosts anticancer effect of 3-bromopyruvate (inhibitor of HK2) by augmenting ER stress-regulated apoptosis	(112)
b-AP15	Selective inhibitor of USP14	Induces ER stress and UPR, blocks WNT1-NOTCH1 signaling, reduces cell viability, fosters apoptosis, and perturbs cell cycle in HCC cells	(113)
Celastrol	Extracted from the root of Tripterygium regelii and Tripterygium wilfordii	Induces ER stress and activates EIF2A-ATF4 axis, leading to activation of PMAIP1 (pro-apoptotic factor) and apoptosis in combination with ABT-737 drug in HCC cells	(114)
Dehydrocostuslactone	Natural sesquiterpene lactone derived from medicinal plants	Blocks HepG2 and PLC/PRF/5 cell proliferation and limits tumor volume by triggering ER stress-induced apoptosis via upregulation of EIF2AK3, ERN1, DDIT3, and increased splicing of XBP1, CASP4 activation	(115)
3,3-Diindolylmethane	Obtained from the digestion of indole-3-carbinol that exists in cruciferous vegetables	Remarkably restrained HCC cell growth, migration, invasion, and proliferation via induction of ER stress-triggered apoptosis in human HCC Huh7 and Hep3B cells	(116)
Ginsenoside compound K	20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol	Induces apoptosis via upregulation of UPR branches and reduces STAT3 levels, blocks colony formation and growth of HCC in human HepG2 and SMMC-7721 cells and human HCC xenografts	(117)
Isovitexin	Glycosylflavonoid derived from hulls in rice Oryza sativa	Suppresses hepatic cancer cell growth in vivo by inducing apoptosis through BAX upregulation, enhanced CASP3 cleavage, increased PARP1 and mitochondrial cytochrome c release, induction of prolonged autophagy, and severe ER stress.	(118)
Meloxicam	Anti-inflammatory drug and selective inhibitor of PTGS2	In combination with sorafenib, induces ER stress-mediated apoptosis in human HCC SMMC-7721 cells and in vivo models	(119)
N-acetylcysteine	Antioxidant	Abates HCC progression via suppressing ER stress and oxidative stress, UPR, and inflammation in TLR2-knockout mice. Reduces SQSTM1 aggregation in liver	(120)
4-O-carboxymethyl ascochlorin	Synthetic ascochlorin derivative	Triggers ER stress and enhances HSPA5 and DDIT3 expression and autophagy protein levels (BECN1, ATG5, MAP1LC3A), resulting in apoptosis and autophagy-dependent cell death in human HCC HepG2 cells	(121)
Piperlongumine	Alkaloid extracted from long pepper fruit	Induces lethal ER stress in HCC in vivo via interacting and inhibiting TXNRD1, resulting in intracellular ROS production	(122)
Safranal	Natural compound extracted from saffron	Induces ER stress-caused apoptosis, caspases activation, and DNA-strand breakage in HCC HepG2 cells	(123)
Scutebarbatine A	Alkaloid found in Scutellaria barbata D. Don	Inhibits HCC cells growth, induces cell cycle arrest and apoptosis via excessive ER stress and UPR induction (upregulates DDIT3, ATF6α, EIF2AK3)	(124)
Sorafenib	Anticancer kinase inhibitor drug	Induces ER stress, leading to apoptosis in human HCC cells, upregulates ERN1. Its combination with chloroquine (autophagy blocker) promotes ER stress-dependent cell death	(125)
SNX-2112	Inhibitor of HSP90AB1	Induces apoptosis via ER stress induction, inhibition of BiP and all UPR branches in SK-Hep1, Huh7, and HepG2 and murine xenograft models	(126)
Sodium demethylcantharidate	Cantharidin derivative	Blocks proliferation of Bel-7402 and SMMC-7721 HCC cells and human HCC xenograft models in a dose- and time-dependent pattern via induction of severe ER stress, leading to apoptosis	(127)
V8	Chemical compound	Induces ER stress-mediated apoptosis via hyperactivation of BiP, PERK, eIF2α, ATF4, and CHOP thus, ceases growth of HCC HepG2 cells in a dose-dependent pattern	(128)