Table 1.

Key ROS-relevant factors and their expression patterns, molecular functions, and potential roles in COVID-19 and lung cancer.

ROS pathway	Relevant factors	Expression patterns	Molecular function	Potential roles in both diseases	Ref.
NRF2	PI3K/Akt	Upregulated in both diseases	PI3K phosphorylate and transfer Phosphatidyl-inositol4,5-bisphosphate (PIP2) into Phosphatidyl-inositol3,4,5-bisphosphate (PIP3), which plays critical role in Akt activation.	An upstream regulator of NRF2, probably inactivates NRF2 in COVID-19, and promotes SARS-CoV-2 entry into the host cell, while activates NRF2 in lung cancer and promotes tumor cell proliferation.	(51, 52, 125, 126)
	KEAP1	Decreased in both diseases	Negative regulator of NRF2, binds to NRF2 and facilitates its ubiquitylation.	It facilitates NRF2 upregulation in lung cancer, and promotes the tumor cell resistance to oxidative stress, while its role in COVID-19 still requires further clarification.	(37, 39, 48)
	NRF2	Activated in COVID-19, while inactivated in lung cancer	As a transcription factor, it regulates the expression of multiple antioxidant genes and viral entry sites.	In COVID-19: the inactivated NRF2 pathways downregulate HO-1 pathway, increase ACE2R expression and decrease anti-oxidase expression.In lung cancer: promotes aggressive proliferation, metastasis of tumors, and tumor resistance to oxidative stress, chemo- and radiotherapy.	(38, 39)
	HO-1	Inactivated in COVID-19	HO-1 degrades heme into biliverdin, iron, and carbon monoxide. Biliverdin is then converted into bilirubin, which has anti-inflammatory, anti-apoptotic, anti-thrombotic, anti-fibrotic, and anti-edema effects.	Increases oxidative stress and magnifies the harmful effect of ROS.	(39, 40)
HIF-1 and hypoxia	mTOR	Activated in both diseases	Activate 4E-BP1	Promote viral replication, angiogenesis, tumor cell proliferation, inhibit apoptosis	(127, 128)
	4E-BP1/ELF-4	Over-expressed in both diseases	4E-BP1 is an mTOR-sensitive protein, which binds to ELF-4 to inhibit the translation initiation of HIF-1α.	Promote tumor cell proliferation and repress protein expression	(58, 129)
	HIF-1	Over-activated in both diseases.	HIF-1 is a transcriptional regulator, controlling the expression of glycolytic genes and facilitates glycolysis	Promote ROS production and increase oxidative stress. Trigger cytokine storm and excessive immune response. Regulate key adaptive mechanisms including glycolysis and angiogenesis, and that drive pro-survival signaling, cell proliferation and metastasis in cancers	(57, 66, 72, 130)
NF-kB	metalloprotease 17 (ADAM17)	Activated in COVID-19	Mediate the splicing of TNFα and sIL-6Rα	Triggers cytokine storm.	(75)
	sIL-6Rα	Accumulated in COVID-19	A combination of TNFα and IL-6Rα	Transduces signal.	(75)
	CBM signalosome	Activated in COVID-19	A combination of CARD and membrane-associated guanylate kinase-like protein, B-cell lymphoma 10, and mucosa-associated lymphoid tissue lymphoma translocation protein 1. It is activated by the binding of AngII to AT1R, and activates IκB kinase complex.	Transduces signal.	(76)
	IL-6	Accumulated in COVID-19	Binds to and activates STAT3.	Triggers cytokine storm and inflammation. Amplifies NF-κB signaling.	(75)
	STAT3	Activated in COVID-19	Promote IL-6 transcription.	Triggers cytokine storm and inflammation. Amplifies NF-κB signaling.	(75)
	IKK	Repressed in both diseases	Phosphorylate, ubiquitylate, and degrade IκB.	Transduces signal.	(76, 91)
	IκB	Repressed in both diseases	Inhibit NF-κB activation.	Transduces signal.	(76, 91)
	NF-κB	Over-activated in both diseases	Regulate downstream antioxidant and pro-oxidant targets to affect intracellular ROS amounts.	In COVID-19: increases oxidative stress, triggers cytokine storm, promotes inflammation.In lung cancer: promotes tumor cell proliferation, metastasis, and inflammation.	(77, 90, 92)