Table 1.

Anticancer molecular target of fisetin and the mechanism of action.

Pathways/Gene	Anticancer Mechanism	Refs.
Inflammation	Plasma levels of hs-CRP as well as interlukin-8 decreased, and the fisetin supplement reduced the values of MMP-7 levels. Fisetin improved the inflammatory status in cancer patients.	[34]
Apoptosis	Treatment with fisetin induced a sub-G1 population in a dose-dependent way. Additionally, the cleavage of poly(ADP-ribose) polymerase (PARP)—a substrate of caspase as well as a marker of apoptosis—was also enhanced. Fisetin caused morphological changes, followed by cell membrane blebbing and shrinkage.	[38]
	Fisetin reduced the mitochondrial membrane potential and the proapoptotic members Bak and Bax and activated caspase-3 and PARP.	[39]
	Fisetin downregulated anti-apoptotic genes and upregulated pro-apoptotic genes. The expression of multiple receptors and ligands involved in extrinsic pathways increased.	[40]
	Fisetin inhibited antiapoptotic Bcl-2 family proteins as well as damaged the mitochondrial transmembrane potential.	[41]
Autophagy	Fisetin induced autophagy, upregulated the autophagy marker LC3B and increased the autophagic flux in pancreatic cancer cells.	[45]
	Fisetin treatment induces the development of autophagic vacuoles in oral cancer cells. Fisetin-induced autophagy in cancer cells was observed via numerous autophagy markers.	[39]
Angiogenesis	Fisetin affected the expression of VEGFR, and this effect was in a dose-dependent manner. Consequently, fisetin downregulated the VEGFR expression.	[47]
	Fisetin inhibited capillary-like tube formation, which was linked with a decreased expression of vascular endothelial growth factor and endothelial nitric oxide synthase.	[48]
	Fisetin treatment caused a dose-dependent decrease in Matrigel plug hemoglobin levels and a decrease in tumor angiogenesis.	[49]
Cell cycle	Fisetin treatment played a role in the cell cycle arrest at the G0/G1 phase. The sub-G1 group meaningfully increased after the treatment of fisetin.	[51]
	Fisetin decreased the total viable cells via G0/G1 phase arrest and induced the sub-G1 phase.	[52]
	Fisetin as well as hesperetin treatment caused a concentration- and time-dependent inhibition of proliferation and induced G2/M arrest.	[53]
PI3K/AKT/ mTOR	Fisetin showed a potential role in the regulation of cancer via inducing apoptosis and regulated autophagy through AKT/NF-κB/mTOR signaling pathways.	[54]
	Fisetin suppress the growth, invasion and migration of pancreatic cancer cells through reducing the PI3K/AKT/mTOR cascade.	[55]
	p-Akt and p-Akt/Akt, p-PI3K and p-PI3K/PI3K and p-mTOR decreased, upregulated Bax and downregulated Bcl-xL after fisetin treatment.	[57]
STAT3	Fisetin downregulated the JAK 1 and STAT3 expression in cancer cells, and fisetin induced apoptosis.	[63]
Wnt/ beta-catenin	Fisetin treatment reduced the levels of Wnt-target genes including cyclin D1 and MMP7.	[68]
	Increasing doses of fisetin were linked with a decrease in cytosolic β-catenin, with a concomitant reduction in nuclear β-catenin.	[69]
Nuclear factor-κB	Nuclear factor-κB was accumulated in the cytoplasm, and the protein expression of NF-κB in the nuclei was decreased by fisetin treatment.	[51]
	Fisetin inhibited the enhancement of IKK, causing a reduction in the stimulation of the NF-κB signaling pathway.	[71]
Nrf2	Fisetin translocated Nrf2 into the nucleus, and the expression of the downstream HO-1 gene was upregulated via the inhibition of the Nrf2 degradation at the post-transcriptional level.	[75]
	Fisetin-induced HO-1 protein expression was reduced through silencing Nrf2.	[76]
JNK/ERK/AP-1	Fisetin upregulated ZAK expression to induce the Hippo pathway and mediated the activation of JNK/ERK to trigger cell apoptosis in an AP-1-dependent manner	[79]