Table 1.

Summary of preclinical antifibrotic effects and underlying mechanisms of naringenin.

Fibrotic disease	Models	In vitro/in vivo	Effects and related mechanisms	Reference
Liver fibrosis	DMN-induced liver damage in rats	In vivo	Reduced hepatic collagen accumulation via the inactivation of HSCs	[6]
	TGF-β1-treated rat HSCs	In vitro	Suppression of ECM expression through inhibition of Smad3 signaling	[87]
	High cholesterol-induced NASH in rats	In vivo	Improvement of liver oxidative and inflammatory status and reduction of hepatic collagen deposition through the downregulation of NF-κB and MMP-2/9, respectively	[88]
	CCl4-induced fibrosis in rats	In vivo	Prevented CCl4-induced liver inflammation, necrosis, and fibrosis through suppression of oxidative stress, NF-κB, TGF-β/Smad3, and JNK/Smad3 pathways	[89, 90]
	Alcohol-induced hepatic damage in mice	In vivo	Attenuated liver inflammation, fibrosis, and hepatocyte apoptosis via decreasing the NF-κB, TGF-β1, and caspase-3 levels	[91]
	CCl4-induced fibrosis in mice, TGF-β1-treated rat HSCs	Both in vitro and vivo	Increased targeting of HSCs, ameliorated liver injury and fibrosis via SPARC-dependent pathways	[92]
	ApoE−/−-induced NASH in mice, mouse hepatocyte AML-12	Both in vitro and vivo	Suppressed hepatic steatosis, oxidative stress, inflammation and fibrosis through modulating hepatic SIRT1-mediated signaling cascades	[93]
	CCl4-induced fibrosis in rats	In vivo	Reduced liver fibrosis and inflammation by the upregulation of MMP-2 activity and downregulation of proinflammatory cytokines levels	[94]
Cardiac fibrosis	Pressure overload-induced cardiac remodeling in mice	In vivo	Attenuated cardiac hypertrophy and interstitial fibrosis via the inhibition of PI3K/Akt, ERK, and JNK signaling	[70]
	TGF-β1-treated CFs	In vitro	Inhibited CF proliferation, differentiation, and collagen synthesis via G0/G1 arrest	[98]
	Hypertension-induced atrial fibrosis in rats, hydrostatic pressure-treated CFs	Both in vitro and vivo	Alleviated the atrial fibrosis in SHRs and inhibited CF proliferation and profibrotic marker expression by inactivating Smad3 signaling	[7]
	AngII-treated CFs	In vitro	Suppressed profibrotic genes expression via inactivating Smad3 signaling	[99]
Lung fibrosis	Bleomycin-induced pulmonary fibrosis in mice	In vivo	Attenuated pulmonary fibrosis through inhibiting TGF-β1 secretion and decreasing regulatory T cells	[5]
	Allergen-induced chronic asthma in mice	In vivo	Inhibited airway remodeling and peribronchial fibrosis probably through reducing Th2 cytokines levels and oxidative stress	[104]
	HDM-induced chronic asthma in mice	In vivo	Improved airway inflammation and fibrosis potentially through inhibiting the expression of proinflammatory cytokines and TGF-β	[105]
	MP-induced pneumonia in mice, MP-treated BEAS-2B cell line	Both in vitro and vivo	Suppressed lung inflammation and fibrosis by inhibition of autophagy activation after MP infection	[106]
	Radiation-induced lung injury in rodents	In vivo	Ameliorated the lung injury including lung fibrosis by lowering IL-1β level and maintaining the homeostasis of inflammatory factors	[107]
Renal fibrosis	Daunorubicin-induced nephrotoxicity in rats	In vivo	Improved nephrotoxicity by reducing renal fibrosis, inflammation, and oxidative/ER stress through mitigating AT1R, ERK1/2-NF-κB p65 signaling pathways	[113]
	A mouse model of UUO, TGF-β1-treated NRK52E cell line	Both in vitro and vivo	Relieved renal fibrosis in vitro and in vivo by blocking Smad3 signaling	[114]
	STZ-induced diabetic nephropathy in rats, high glucose-treated cell line	Both in vitro and vivo	Attenuated the deposition of ECM in vitro and in vivo and inhibited cell proliferation in vitro, through let-7a-mediated inhibition of TGF-β1/smad signaling	[115]
	A rat model of renovascular hypertension	In vivo	Ameliorated hypertensive renal damage, including interstitial fibrosis, by modulating the balance of components of the renin-angiotensin system	[116]
	A mouse model of lupus	In vivo	Reduced the autoimmunity and prevented kidney damage including fibrosis by modulating T-cell subsets and cytokine profile	[117]
Skin fibrosis	Mechanical stretch-induced hypertrophic scars in mice	In vivo	Attenuated skin fibrosis and inhibited scar formation via the inhibition of dermal fibroblast activation and local inflammation	[124]

Abbreviations used are DMN: dimethylnitrosamine; HSCs: hepatic stellate cells; ECM: extracellular matrix; NASH: nonalcoholic steatohepatitis; SPARC: secreted protein acidic and rich in cysteine, CFs: cardiac fibroblasts; HDM: house dust mite; MP: mycoplasma pneumonia; ER: endoplasmic reticulum; STZ: streptozotocin.