Table 1 Pharmacological effect of TFEB activators for the treatment of ALP dysfunction

Curcumin (1)

Cancer

Directly bind to TFEB

Human colon cancer HCT116 cells and MEFs

Enhance autophagic flux, promote lysosomal function

[54]

Curcumin analog C1 (2)

1. AD

2. PD

Directly bind to TFEB

1. 5×FAD mice, P301S mice, 3xTg-AD mice

2. SH-SY5Y cells, iPSC-derived DA neurons, mice nigral DA neurons, 6-OHDA/AA-lesioned models

1. Reduce APP, CTF-β/α, Aβ and Tau aggregates, improve motor and cognitive function

2. Enhance autophagy, reduce neuronal death, rescue behavioral abnormality

[55, 56]

Curcumin analog E4 (3)

PD

Inhibit Akt-mTORC1

N2a cells, HeLa cells, PC12 cells

Promote autophagic flux and lysosomal biogenesis, reduce α-synuclein, protect against MPTP toxicity

[57]

Resveratrol (4)

Atherosclerosis

HUVECs

Promote autophagic flux, attenuate endothelial oxidative injury

[49]

Oleuropein aglycone (5)

Cardiovascular disease

Cardiomyocytes

Promote autophagic flux, restore autophagy impairment, protect from cardiotoxicity

[48]

Chlorogenic acid (6)

AD

Inhibit mTOR

Aβ25-35-induced SH-SY5Y cells APP/PS1 mice

Ameliorate cognitive deficits, neuronal injury, and Aβ plaque deposition, inhibit The production of autophagosomes, improve autophagic flux, enhance lysosomal activity

[58]

Genistein (7)

MPS

HDFa cells, HeLa cells, MEFs

Inhibit GAG synthesis, enhance lysosomal hydrolases

[59]

Genistein (7) and kaempferol (8)

MPS

Inhibit mTOR

HDFa and MPS II cells

Stimulate the expression of genes coding for GAG degrading enzymes

[60]

Quercetin (9)

Neuronal tissues

Inhibit mTORC1

Retinal pigment epithelium cells

Enhance autophagy, degrade phagocytosed photoreceptor outer segments

[61]

Fisetin (10)

AD

Inhibit mTOR

Mouse cortical neuronal cells, rat primary cortical cells, HEK293 cells

Enhance autophagy, degrade p-tau and sarkosyl insoluble tau

[62]

Corynoxine isomers (11–12)

AD

N2a cells, Tg2567 mice

Decrease Aβ, APP and CTF, promote autophagy and lysosome biogenesis

[63]

Fangchinoline (13)

Cancers

NSCLC cells

Inhibit the fusion of autophagosome and lysosome, decrease autophagic flux, affect lysosome function

[64]

Pseudoginsenoside-F11 (14)

AD

Inhibit mTOR

Microglial cells

Increase uptake and degradation of oligomeric Aβ, promote maturation of endosome, improve lysosomal function

[65]

Gypenoside XVII (15)

AD

PC12 cells expressing the Swedish mutant of APP695, APP/PS1 mice

Improve autophagic flux, enhance lysosome biogenesis, degrade Aβ, restore the spatial learning and memory

[66]

Hinokitiol (16)

Cancers

NSCLC cells, HCC827 cells, HeLa cells, MEFs

Promote autophagy and lysosomal biogenesis, induce cancer cells death

[67]

Paeoniflorin (17)

SBMA

Increase the expression of NF-YA to upregulate TFEB

NSC34 cells stably expressing AR-97Q, AR-97Q mice

Activate autophagy, inhibit aggregation of the mutant AR protein, ameliorate motor phenotypes

[37]

Oblongifolin C (18)

Cancers

Inhibit mTORC1

HeLa cells, L929 cells, MEF cells, HEK293T cells

Improve autophagosome maturation, block autophagosome–lysosome fusion, suppress HeLa cells growth

[68]

Ouabain (19)

AD

Inhibit mTOR and Na⁺/K⁺-ATPase

HeLa and SH-SY5Y cells, primary cortical neurons, drosophila melanogaster tau model, Tau-P301L mice

Relieve neuronal damage, reduce p-Tau aggregates, improve a rough-eye phenotype, restore memory performance

[69]

Cardiac glycoside-ingenol derivative Hep14 (20)

AD

Activate PKC, PKC inactivate GSK3 leading to TFEB dephosphorylation

HeLa and HepG2 cells, APP/PS1 mice

Activate lysosomal gene expression, promote lysosome-dependent clearance of lipid droplets and aggregated proteins

[70]

Digoxin (21)

Metabolic disorders

Ca²⁺-dependent TFEB dephosphorylation to activate TFEB

HepG2 Cells, C. elegans, C57BL/6 J mice

Ameliorate metabolic syndromes, extend lifespan

[71]

Trehalose (22)

1. ALS

2. ALS, SBMA

3. Batten disease

1. mTOR-independence

2. PPP3B mediated TFEB dephosphorylation and lysosomal stress

3. inhibit Akt

1.SH-SY5Y and Hella cells

2. NSC34 cells

3. Cln3Dex7-8 mice

1. Enhance autophagy flux, eliminate TDP-43 aggregates

2. Degrade misfolded protein including AR. Q46, TDP-43, and mutant SOD1

3. Enhance cellular clearance of proteolipid aggregates, reduce neuropathology

[38, 72, 73]

Cinnamic acid (23)

AD

Activate PGC-1α to transcriptionally upregulate TFEB expression

Mouse primary brain cells, 5xFAD mice

Induce lysosomal biogenesis, reduce the amyloid plaque burden, improve memory and behavioral performance

[74]

Salidroside (24)

Cancers

Induce ROS generation, ROS activate the TFEB signal pathway

SW1353 cells

Induce autophagy, promote apoptosis

[75]