. 2023 Sep 15;8:352. doi: 10.1038/s41392-023-01570-w

Table 2.

ER stress is effective therapeutic target for ocular diseases

Disease	Agent	Facilitate ER stress (+)/inhibit ER stress (−)	Target	Pathway	Function in ocular diseases	Used in other fields	Reference
Glaucoma	4-PBA	−	Myocilin, MMP2, and MMP9	The whole ER stress pathway	Facilitation of myocilin outflow and degradation in TM	Heart, lung, and kidney injury	^152,153
Glaucoma	4-Br-BnIm	−	GRP94	ER stress chaperone	Inhibition of GRP94 lower the levels of mutant myocilin and save RGCs	Null	¹⁴⁹
Glaucoma	Astragaloside-IV	−	MMP3 and MMP9	The whole ER stress pathway	Rescue TGF-β2 induced ocular hypertension by relieving RM damage	In renal and cardiac diseases	¹⁵³
Glaucoma	shp2	+	PERK	PERK pathway BDNK/TrkB pathway	Knock down of Shp2 relieve ER stress	Cancer for immunotherapy, human development disorders, and aggravating psoriasis	^{122,472–474}
Glaucoma	CRISPR-Cas9	−	Myocilin/HRH1/CHOP/ATF4	The whole ER stress pathway	Remove MYOC mutation/alleviation of Ca²⁺ release/knockout UPR molecules to protect TM cells and RGCs	Null	^77,108,175
Glaucoma	TMAO	−	Unfolded myocilin	ER chaperone	Facilitate myocilin outflow	In urethral cycle disorders for clinical use	¹⁵¹
Glaucoma	LDN-0060609	−	PERK	PERK-ATF4-CHOP	Relieve ER stress and protect TM cells	In Alzheimer’s disease	¹⁵⁰
Glaucoma	siRNA	−	Mutant MYOC	The whole ER stress pathway	Repopulation of TM cells, prevention of RGCs loss, and recovery of IOP	–	⁷⁵
Glaucoma	siRNA	−	PKR	The PERK/ eIF2α/ATF4/CHOP pathway	Relieve ER stress and protect RGCs	–	¹⁷⁶
Glaucoma	Imidazolo-oxindole derivative	−	PKR	The PERK/ eIF2α/ATF4/CHOP pathway	Relieve ER stress and protect RGCs	–	¹⁷⁶
Glaucoma	Human trabecular meshwork stem cells	−	TM tissue	The whole ER stress pathway	Relieve of ER stress, replication of endogenous TM cells, and the restoration of the ECM structure	–	^161,162
Glaucoma	Induced pluripotent stem cells	−	TM tissue	The whole ER stress pathway	Relieve of ER stress and supplement of TM cells	Not used in clinic	¹⁶³
Glaucoma	Mesenchymal stem cells	−	TM tissue	The whole ER stress pathway	Relieve of ER stress and supplement of TM cells and protection of RGCs	Not used in clinic	¹⁶⁴
Glaucoma	Exosomes derived from bone marrow mesenchymal stem cells	−	TM tissue	The whole ER stress pathway	Protection of TM cells from ER stress	Not used in clinic
Glaucoma	Non‐pigmented ciliary epithelium derived exosomes	−	ECM degradation and	WNT/β‐catenin pathway and nrf2 downstream and the whole ER stress pathway	Decreased ECM and ER stress in TM tissue, and alleviation of inflammation	–	¹⁶⁷
Glaucoma	Adipose-derived stem cells	−	TM tissue	The whole ER stress pathway	Protection of TM cells from ER stress	–	¹⁶⁶
Glaucoma	Combining stem cell therapy with superparamagnetic iron oxide nanoparticles	−	TM tissue	Relieve the whole ER stress pathway	Drive the homing of stem cell and preserve TM tissue	–	¹⁶⁵
Glaucoma	Amoxapine/desloratadine/maprotiline	−	RXR	PERK-ATF4-GADD34	Relieve ER stress	In relapsing–remitting multiple sclerosis, hematoma, diabetes, and lung cancer and	¹⁰⁸
Glaucoma	Valdecoxib	−	COX2	PERK/ATF4/CHOP pathway	Reduce RGC apoptosis	In the treatment of osteoarthritis (OA) and arthritis	¹⁷⁷
Glaucoma	KUSs	−	ATPase	Autophagy	Protection of RGCs, amacrine cells, and photoreceptors	Ischemic neuropathy	¹⁷⁰
Glaucoma	p58^IPK overexpressed by AAV	−	Neurotrophin	ER protein chaperon	Elevation of RGCs survival rate through refolding protein and inhibition of ER stress	–	¹¹⁵
Glaucoma	Resveratrol	−	RXRs and HDAC1	The whole ER stress pathway	Reduce ER stress-induced RGC apoptosis	–	¹⁷⁸
Glaucoma	Tubacin	−	HDAC6	The whole ER stress pathway	Reduce oxidative stress and ER stress to protect RGCs	In the treatment of bipolar disorder and epilepsy	¹³⁴
Glaucoma	Valproate	−	HDAC	Bip and CHOP	Reduce oxidative stress and ER stress to protect RGCs	In the treatment of bipolar disorder and epilepsy	¹³⁶
Glaucoma	Rapamycin	−	Autophagy	mTOR pathway	Restore autophagy caused by OPTN mutation and relieve ER stress	–	¹⁰²
Glaucoma	Trehalose	−	Autophagy	Autophagy independent of mTOR pathway	Restore autophagy caused by OPTN mutation and relieve ER stress	–	¹⁰²
Glaucoma	Nanoparticles	−	ER stress and oxidative stress	ROS and the whole ER stress pathway	Inhibit ER stress and oxidative stress at the same time	–	¹⁷⁹
Glaucoma	Pentazocine	+	S1R	IRE1/XBP1 pathway	Upregulate the protective IRE1/XBP1 pathway and reduce the other two to protect RGCs	–	¹¹³
Glaucoma	BDNF/MANF/rhNGF	−	Neurotrophin	The whole ER stress pathway	Relieve ER stress to protect RGCs	–	^117,120,181
Diabetic retinopathy (DR)	4-PBA	−	The whole ER stress pathway	The whole ER stress pathway	Inhibit ER stress and protect retinal neuron	Heart, lung, and kidney injury	^152,153,187
DR	TUDCA	−	TGR5	The whole ER stress pathway	Alleviate ER stress by inhibiting Grp78 translocation and reduce VEGF that protect inner BRB	–	²⁴⁹
DR	Nobiletin	−	GADPH translocation	The whole ER stress pathway	Protect Muller glia and recover VEGF/PEDF, which protect iBRB	–	²⁰⁷
DR	Ghrelin	−	GHSR-1a	PERK pathway	Inhibit ER stress in endothelial cells to protect inner BRB	–	²⁵⁰
DR	Astragalus polysaccharide	−	miR-204	miR-204/SIRT1 axis	Alleviate inflammation and reduce the apoptosis of RPE cells	In tumor treatment	^189,244,245
DR	Lactucaxanthin	−	ER stress, oxidative stress and inflammation	The whole ER stress pathway	Decrease vascular leakage due to rescue the destructed tight junction between RPE cells	For antioxidants, antidiabetic substance, and anticancer drugs	^{208,233,246–248}
DR	CRISPR-Cas9 technology	−	IRE1α	IRE1α/XBP1STING pathway	Protection of endothelial cells to protect iBRB	–	²¹³
DR	siRNA	−	TCF7L2	ATF6 pathway	Protect vascular endothelial cells and iBRB	–	²¹⁷
DR	P58^IPK	−	neurotrophin	PERK/eIF2α pathway	Protect vascular endothelial cells by inhibiting VEGF production	–	²⁵¹
DR	Liraglutide	−	Trx-ASK1	Trx-ASK1complex/ER stress	Protect RGCs by inhibiting ER stress	In T1DM, T2DM, and obesity	^475,476
DR	Sulforaphane	−	AMPK	Inhibit ER stress by AMPK pathway	Protect retinal cells including photoreceptors by reducing inflammation, oxidative stress, and ER stress	In age-related diseases and neuroinflammation diseases	²⁵⁴
DR	Melatonin	−	PERK pathway and Bip	PERK pathway	Prevent RGCs death via inhibiting ER stress	In the control of the circadian rhythm, immune enhancement, and antioxidant, anti-aging, and antitumor effects	²⁵⁶
DR	Stem cell therapy	−	Adipose-derived mesenchymal stem cells	Combining the neuroprotective effect with melatonin	Neuro protection	–	²⁵⁶
DR	Chrysin	−	UPR and AGE-RAGE	Reduction of UPR and activation of AGE-RAGE	Save the BRB by rescuing RPE and reduction of VEGF	In degenerative disorders and provides cytotoxic and anti-inflammatory functions	¹⁹⁴
DR	Penicillamine	−	Elevated copper	The whole ER stress pathway	Protect BRB by saving RPE via alleviating ER stress and MFN2	–	¹⁸⁶
DR	Neurotrophin-4	−	Neurotrophin	The whole ER stress pathway	Protect RGCs via inhibiting ER stress	–	²⁴¹
DR	NT4-polyamidoamine (PAMAM) electrostatic complex	−	Neurotrophin packed in nanoparticles	The whole ER stress pathway	Protect RGCs via inhibiting ER stress	–	²⁵²
Age-related macular degeneration (AMD)	Grape polyphenols	−	ER stress and inflammation	The whole ER stress pathway	Prevent neovascularization and protect RPE	–	²⁹³
AMD	Curcumin	−	ER stress	The whole ER stress pathway	Protect RPE from ER stress damage	–	²⁹⁴
AMD	ISR inhibition	−	ER stress	The whole ER stress pathway	Prevent neovascularization via inhibition of ER stress, like ATF4	–	²⁷⁵
AMD	Paeoniflorin	−	CaMKII/AMPK	The whole ER stress pathway	Protect RPE	–	²⁹⁵
AMD	Propofol	−	UPR pathway	The whole ER stress pathway	Protect RPE	–	²⁹⁶
AMD	Humanin	−	UPR pathway	The whole ER stress pathway	Protect RPE	–	²⁹⁷
AMD	Human umbilical cord mesenchymal stem cell-derived exosomes	−	miR-27b	The whole ER stress pathway	Secretion of miR-27b to inhibit fibrosis-induced ER stress	–	²⁹⁹
AMD	Human retinal progenitor cells	−	UPR pathway	The whole ER stress pathway	Supplement with neural cells to compensate ER stress-induced cell loss	–	³⁰⁰
AMD	Taurine	−	Calpain	Upregulate calpain to inhibit ER stress	Protect RPE	–	²⁹⁸
RP	4-PBA	−	UPR pathway	The whole ER stress pathway	Protect the whole retinal cell via inhibition of ER stress	Heart, lung, and kidney injury	^325,326
RP	TUDCA	−	UPR pathway	The whole ER stress pathway	Protect the whole retinal cell via inhibition of ER stress	Studied in many neurodegenerative diseases	^325,326
RP	Rapamycin	−	mTOR	PI3K/AKT/mTOR	Inhibit ER stress and the downstream inflammation in RPE and photoreceptors	Lifespan, cardiac disease/function, central nervous system, immune system, and cell senescence	⁴⁷⁷
RP	PP242	−	mTOR	PI3K/AKT/mTOR	Inhibit ER stress and the downstream inflammation in RPE and photoreceptors	In colon cancer and gastric cancer	^478,479
RP	AICAR	−	AMPK	CAMKKβ/AMPK/mTOR	Inhibit ER stress and restore autophagy	In heart diseases	⁴⁸⁰
RP	Salubrinal	−	peIF2α	PERK-ATF4-CHOP	Reduce ER stress in RPE and photoreceptors	–	³⁰⁸
RP	Bilberry extract	−	UPR pathway	The whole ER stress pathway	Protect RGC loss induced by ER stress	–	³¹²
RP	HSPA4L	−	PRPF31 mutant aggresomes	Protein chaperon	Transport PRPF31 mutant aggresomes to nuclear which protect RPE	Null	⁴⁸¹
RP	CRIPR/Cas9	−	RHO mutation	UPR pathway	Knock out mutant RHO to reduce ER stress in photoreceptors	–	³²⁸
RP	siRNA	−	RHO mutation	UPR pathway	Knock out mutant RHO to reduce ER stress in photoreceptors	–	³²⁹
RP	Stem cell therapy	−	Stem cell differentiated into RPE cells	The whole ER stress pathway	Supplement with RPE, which prevent the retinal cell loss induced by ER stress	–	^{331–333,335}
RP	Exosomes derived from mesenchymal stem cell and RPE	−	UPR pathway	The whole ER stress pathway	Prevent the whole retina from the damage of ER stress	–	^337–339
RP	Optogenetics	−	Non-photosensitive retinal cells	The whole ER stress pathway	Converting non-photosensitive retinal cells to photoreceptors, which escape the ER stress damage resulted from RHO mutation	–	³⁴²
ACHM	Fenretinide	+	ATF6	ATF6 pathway	Increase the expression of ATF6 to protect cone photoreceptors	–	³⁵³
ACHM	AA157	+	ATF6	ATF6 pathway	Increase the expression of ATF6 to protect cone photoreceptors	–	³⁴⁹
ACHM	Rp-8-Br-cGMPS	−	cGMP	cGMP/PKG/ RyR2	Elevate of intracellular Ca²⁺ and abolish the channel upregulation in CNG channel deficiency to reduce ER stress in cone cells	In vascular and muscle field	³⁴⁸
ACHM	KT5823	−	cGMP	cGMP/PKG/ RyR2	Elevate of intracellular Ca²⁺ and abolish the channel upregulation in CNG channel deficiency to reduce ER stress in cone cells	In Marfan syndrome, thyroid cancer, and breast cancer	³⁴⁸
RP	AAV	−	CNGB3	The whole ER stress pathway	Protect cone photoreceptors	–	³⁵⁶
RP	CRISPR/Cas9	−	PDE6	The whole ER stress pathway	Protect cone photoreceptors	–	³⁵⁷
Cataracts	4-PBA	−	Protein chaperon	The whole ER stress pathway	Reduce EMT via inhibition of ER stress and reduce opacity in lens	Heart, lung, and kidney injury	³⁷⁷
Cataracts	Pentazocine	−	S1R	The whole ER stress pathway	Relieve ER stress, OS, and cell apoptosis in lens cell	–	³⁷⁸
Cataracts	Iontophoresis	−	Delivery system	The whole ER stress	Combining it with ER-targeted drugs to reduce opacity in lens	–	³⁷⁹
Uveitis	TUBCA	−	IRE1α	IRE1/NOD2 pathway and NLRP3 inflammasomes	Downregulation of ER stress via inflammation inhibition	–	³⁸²
Uveitis	Galectin-3	−	UPR pathway	The whole ER stress pathway	Downregulation of ER stress in BS	–	³⁹⁰
Uveitis	Mesalazine	−	UPR pathway	The whole ER stress pathway	Alleviation of inflammation via ER stress reduction in BS	–	³⁸⁹
Uveal melanoma (UM)	4-PBA	−	UPR pathway	The whole ER stress pathway	Effectively inhibit ER stress in BRAF-mutated melanoma	Heart, lung, and kidney injury	⁴⁰⁸
UM	Pemetrexed	+	CHOP	CHOP/ NOXA/ Mcl-1 pathway	Facilitate ER stress-induced intrinsic apoptosis	–	⁴¹⁰
UM	Navitoclax	−	PERK	PERK pathway	Blocking ER stress-induced drug resistance to facilitate tumor apoptosis	–	⁴⁰⁷
UM	Combining targeted ER stress therapy with immunotherapy	−	UPR pathway	The whole ER stress pathway	Inhibition of ER stress, which facilitates immunotherapy effects	–	⁴¹²
UM	Nanosystems	−	ER	The whole ER stress pathway	Directly inhibit ER stress to strengthen antitumor drugs effects	–	⁴¹²
UM	SCD1 inhibitor	−	UPR pathway	The whole ER stress pathway andβ-catenin signaling	Production of antitumor CD8⁺ T cell by inhibiting ER stress	In human colon cancer	⁴¹²
Corneal dystrophy	4-PBA	−	UPR pathway	The whole ER stress pathway	Reinforce ER stress and degrade TGFBIp by relieving ER stress	Heart, lung, and kidney injury	⁴²⁷
Corneal dystrophy	Melatonin	−	The UPR pathway	IRE1α/XBP1 pathway	Inhibition of ER stress to save GCD2 corneal fibroblasts	–	⁴³¹
Corneal dystrophy	Mitochondrial ROS quencher MitoQ	−	Bip and GADD153	The whole ER stress pathway	Restore mitochondria function by inhibiting Bip and GADD153	–	⁴¹⁶
Corneal dystrophy	Glafenine	−	Mutant SLC4A11	The whole ER stress pathway	Facilitate SLC4A11 folding, which inhibit ER stress-induced cell loss	–	⁴³⁵
Corneal dystrophy	Mesenchymal stem cell-derived extracellular vesicles	−	The UPR molecules	The whole ER stress pathway	Contain miRNA-targeted ER stress while facilitating cell survival in cornea	–	⁴³⁶
Myopia	Salidroside	−	HIF-1α	HIF-1α/eIF2α	Inhibition of hypoxia-induced ER stress to prevent sclera remodeling	–	^463,464
Myopia	Formononetin	−	HIF-1α	HIF-1α/eIF2α	Inhibition of hypoxia-induced ER stress to prevent sclera remodeling	–	^463,464
Myopia	4-PBA	−	The UPR pathway	The whole ER stress pathway	Normalize the vitreous chamber depth and retinal thickness via inhibition of ER stress	Heart, lung, and kidney injury	⁴⁵⁹
Myopia	TUDCA	−	The UPR pathway	The whole ER stress pathway	Normalize the vitreous chamber depth and retinal thickness via inhibition of ER stress	–	⁴⁵⁹
Myopia	CRIPR/Cas9	−	PERK and ATF6	PERK and ATF6 pathway	Normalize the vitreous chamber depth and retinal thickness via inhibition of ER stress	–	⁴⁵⁸