Table 1.

Molecules targeting TFEB and their respective mechanisms and function.

Synthetic molecules targeting TFEB
Name	Mechanism	In vitro study	In vivo study	Ref
3,4-dimethoxychalcone (3,4-DC)	Inhibits mTOR Promotes TFEB nuclear translocation	HepG2 and U2OS cells: Enhances autophagy	Attenuates myocardial infarction and improves the efficacy of chemotherapy drugs	[59]
Alexidine, and ikarugamycin	Alexidine and Ikarugamycin: Ca2+-CaMKKβ/AMPK/mTORC1 Promote TFEB nuclear translocation	HeLa cells: Enhance autophagy	Attenuate metabolic disorders in HFD-fed mice and extend lifespan in C. elegans	[62]
Ezetimibe	Activates AMPK Promotes TFEB nuclear translocation	Mouse hepatocytes and human hepatoma cells: Increases autophagy and ameliorates lipid accumulation and apoptosis Macrophages: Inhibits the NLRP3 inflammasome-IL1β pathway	Attenuates lipid accumulation, inflammation, and fibrosis in liver-specific Atg7 wild-type and haploinsufficient mice	[61]
Formononetin	Activates AMPK Promotes TFEB nuclear translocation	HepG2 and mouse hepatocytes: Facilitates lysosome biogenesis and lipophagy	Inhibits HFD-induced hepatic steatosis and lipid disorders in mice	[65]
Gemfibrozil	Activates PPARα-RXRα-PGC1α Increases TFEB expression	Astrocytes: Enhances lysosomal biogenesis	Increases lysosomal biogenesis in the cortex in mice	[34]
MSL	Promotes TFEB nuclear translocation	HeLa cells: Enhances autophagy and decreases intracellular lipid accumulation	Improves metabolic disorders in ob/ob mice	[63]
Tubastatin A	Increases TFEB acetylation Promotes TFEB nuclear translocation	NRK-52E cells: Attenuates cell death	Protective in rat experimental kidney disease	[66]
Natural molecules targeting TFEB
Aspirin	Activates PPARα Increases TFEB transcription	Mouse primary astrocytes: Increases lysosomal biogenesis	Reduces the amyloid burden in the hippocampus of 5XFAD mice	[67]
Carbon monoxide	Activates PERK-calcineurin Promotes TFEB nuclear translocation	Hepatocytes: Increases mitophagy	Attenuates inflammatory liver injury induced by LPS/D-GalN in mice	[64]
Curcumin analog-C1	Binding to N-terminal of TFEB protein Promotes TFEB nuclear translocation	N2a cells and HeLa cells: Promotes autophagy flux and lysosomal degradation/biogenesis	Activates TFEB and enhances autophagy in rat brains	[68]
Digoxin	Digoxin: Ca2+-Calcineurin Promotes TFEB nuclear translocation	HeLa cells: Enhances autophagy	Attenuates metabolic disorders in HFD-fed mice and extend lifespan in C. elegans	[62]
Gypenoside XVII	Promotes TFEB nuclear translocation by releasing TFEB from TFEB/14-3-3 complexed	PC12: Increases autophagy and eliminates AβPP, Aβ40, and Aβ42 protein	Prevents the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice	[69]
HEP14 and HEP15	Activate PKC-GSK3β Promote TFEB nuclear translocation	HeLa cells: Enhance lysosome biogenesis	Attenuate the formation of amyloid β (Aβ) plaques in APP/PS1 mouse brains	[21]
HPβCD	Depletes intracellular cholesterol and inhibits mTORC1 Promotes TFEB nuclear translocation	VSMCs: Enhances autophagy and inhibits apoptosis HeLa, LINCL fibroblasts, and macrophages: Enhances autophagy and suppresses macrophage M2 polarization.	Inhibits abdominal aortic aneurysm formation and progression in mice Inhibits breast tumour growth in mice	[12,15,60]
Procyanidin B2	Possible direct binding Promotes TFEB nuclear translocation	HepG2: Enhances lysosomal function	Attenuates HFD-induced hepatic steatosis in mice	[70]
Trehalose	Activates calcium-dependent phosphatase PPP3/calcineurin or inhibits Akt Promotes TFEB nuclear translocation	NSC34 cells, macrophages, and HeLa cells: Promotes clearance of neurotoxic misfolded proteins Enhances autophagic flux	Prolongs the lifespan in the Batten disease mouse model. Attenuates atherosclerosis and cardiac remodelling in mice. Suppresses vascular neointimal formation	[47,58,71,72]

Abbreviation: HFD: high-fat diet; HPβCD: 2-Hydroxypropyl-β-cyclodextrin; HEP14: 5β-O-angelate-20-deoxyingenol and HEP15: 3β-O-angelate-20-deoxyingenol; Trehalose: α-D-glucopyranosyl α-D-glucopyranoside; MSL: 4-(4-fluorophenyl) sulfonyl-5-methylthio-2-phenyloxazole; PC12: rat pheochromocytoma cell line; PERK, protein kinase RNA-like endoplasmic reticulum kinase; CAMKKβ, calcium/calmodulin-dependent protein kinase kinase 2; PPARα, peroxisome proliferator-activated receptor-alpha; RXRα, retinoid X receptor-alpha; AMPK, 5′ AMP-activated protein kinase; GSK3β, glycogen synthase kinase 3 beta; PKC, protein kinase C.