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

From: Transcription factor EB agonists from natural products for treating human diseases with impaired autophagy-lysosome pathway

Compound Disease Mechanism involved in activation of TFEB Model Effects References
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]
  1. ‘–’ indicates absence of data