Table 1.

Main factors implicated in renal fibrosis.

Class	Name	Pathways	Action	Evidence
Wnt/β-catenin	TRPC6 knockout	Wnt/β-catenin downstream signaling	Ameliorates renal fibrosis and α-SMA expression	[40]
	Snail1 inhibition by Eucalyptol		Loweres α-SMA expression in tubulointerstitial space	[26]
	Snail upregulation		Seen in largest cysts from polycystic renal disease	[28]
	PAI-1 knockout		Ameliorates tubulointerstitial fibrosis via FMT inhibition and lower collagen I deposition	[37]
	MMP-7 knockout		Protects from podocyte destruction	[33]
	MMP-7 upregulation		Promotes apoptosis and FMT	[32]
ANG II	ANG II upregulation	JAK and MAPK activation Increased intracellular Ca2+ influx Upregulation of TGF-β/SMAD2/SMAD3 signaling	Renal fibrosis	[44]
	Oxymatrine	ANG II and aldosterone inhibition	Overproduction of fibronectin, collagen I, PAI-1 and PAI-2	[45]
TGF-β1/SMAD signaling	POU4F1 silencing	SMAD3 downstream signaling	Prevents MMT	[70]
	Src inhibition		Prevents MMT	[71]
	SET9 activation		Increases SMA expression	[49]
	SMAD4 inhibition		Lowers renal fibrosis in UUO mouse models	[53]
	SMAD3 inhibition		Lowers renal fibrosis in diabetic, obstructive and hypertensive nephropathy	[46,51,52]
	GSK3β inhibition		Induces higher CREB activity with lower CBP, essential in SMAD3 activation	[50]
	Snail1 knockout		Reduces renal fibrosis in mice obstructive nephropathy	[29]
	CDKIs: p16, p21, p27, p38		Induces tubular epithelial cell death, through G1 cell cycle arrest and are involved in kidney ageing	[72]
	PAI-1 activation	Klotho inhibition with TGF-β and p53 upregulation	Promotes kidney fibrosis	[73]
	CRP	Smad activation via CD32b-ERK/p38 MAP kinase crosstalk pathway	Promotes kidney inflammation and fibrosis	[74]
	miR-21 knockout	SMAD3 downstream signaling Through PTEN/Akt pathway	In vivo studies—abolished FMT In vitro studies—alleviates renal fibrosis in obstructive nephropathy	[57]
	miR-192	SMAD3 downstream signaling	High serum/intrarenal and urinary levels were associated with higher grades of tubulointerstitial fibrosis	[58]
	Exo/miR-29	SMAD3 downstream signaling	MiR-29 exerts anti-fibrotic effects through TGF-β1 inhibition	[60]
	Erbb4-IR	SMAD dependent lncRNA	Promotes renal fibrosis in diabetic and obstructive nephropathy Erbb4-IR inhibition alleviates renal fibrosis via miR-29 upregulation	[75]
	Arid2-IR		Protective in cell cycle control	[61]
	GAS5		Inhibits TGF-β1 and is downregulated by SMAD signaling Evidences blocked renal fibrosis in vitro studies	[62]
Cell death pathways	Fn-14 knockout gene	TWEAK pathway	Reduces death of tubular epithelial cells	[76]
	Pannexin-1 inhibition	MAPK/ERK pathway	Inhibits ferroptosis and evidences decreased serum creatinine, cell necrosis and melondialdehyde expression	[77]
	Ferrostatin-1	Ferroptosis inhibitor	Lowers tissue renal damage in mouse models with cisplatin-induced AKI	[78]
	VDR	Inhibits GPX4—key control of ferroptosis	Knockout for VDR in mice evidenced worsened renal injury Paricalcitol activates VDR and evidenced lower AKI stage after cisplatin treatment	[79]
	XJB-5-131	Inhibits ferroptosis	Decreases AKI stage, attenuated inflammation and promoted tubular epithelial cell proliferation	[80]
	Tocilizumab	IL-6 and ferroptosis inhibition	Alleviates renal injuries in obstructive nephropathy	[81]
	Legumain	Downregulate GPX4—key control of ferroptosis	Alleviates AKI stage in rats	[82]
	miR-387a-3p knockout	Ferroptosis transcription factor	Downregulates IRI on mouse models	[83]
	miR-182-5p knockout	Ferroptosis transcription factor	Downregulates IRI on mouse models	[83]
	Necrostatin-1	RIPK1 inhibition	Ameliorates IRI via HIF-1α/mir-26a/TRPC6/PARP1 inhibition	[84]
	hsa-miR-500a-3P knockout (mRNAs for MLKL)	SMAD3 downstream signaling	Alleviates kidney injury by necroptosis inhibition	[67]
	RIPK upregulation	SMAD3 downstream signaling	Promotes necroptosis	[69]
Hypoxia pathways	HIF-1/2α stimulation	miR-21 upregulation and VEGF upregulation	Renoprotective due to increased angiogenesis	[85]
	miR-493 overexpression	STMN-1 inhibition	Is stimulated by hypoxia and induces renal fibrosis through G2/M cell cycle arrest	[86]
	TRC160334	PHD inhibitor	Induce HIF-1α upregulation with reduced IRI	[87]
	PINK1/PARK2	Upregulated mitophagy	Inhibits Drp1, renal inflammation and tubular epithelial cell apoptosis	[88,89]
	Drp1 knockout	Mitochondrial fragmentation	Ameliorates renal inflammation, renal injury and renal fibrosis	[90]
	Mst1 knockout	Upregulates mitophagy	Renoprotective via AMPK and OPA1 downregulation	[91]
	BNIP3 knockout	Downregulates mitophagy	Increased ROS, damaged mitochondria and inflammatory renal response	[92]
	miR-668	HIF-1α downstream signaling	Renoprotective due to reduced apoptosis and mitochondrial fragmentation	[93]
	VEGF inhibition		Induces thrombotic microangiopathy	[94,95]
	VEGF upregulation		Induces collapsing glomerulopathies	[96]
	VEGF upregulation		Increases EMT via upregulation of matrix metalloproteinases	[97]
	SAR131675	VEGF receptor—tyrosine kinase inhibition	Reduces apoptosis, lymphangiogenesis, inflammation and renal fibrosis	[98]
G2/M cell cycle arrest	GC1 inhibition	TASCC inhibition	Ameliorates renal fibrosis	[99]
	MYD88 knockout	TLR/IL-1R downstream signaling and NF-κB upstream signaling	Ameliorates renal fibrosis	[100]
Immunological pathways	NOX-D21	C5a/C5aR inhibition	Attenuates tubulointerstitial fibrosis in diabetic nephropathy	[101]
	Orai1 knockout	Th17 inhibition	Alleviates renal fibrosis	[102]
	Flt3 inhibitor	DCs downstream signaling	Reduces proinflammatory cytokines and chemokines, TNF-α, IL-6 and IL-1β	[103]
	IL-10	Cd4+ T cell activation	Reduces renal fibrosis in diabetic nephropathy	[104]
	IL-10 co-vaccination		Reduces tubular damage in SLE nephropathy on mouse models	[105]
	Double negative T cells upregulation		PTECs-reduced apoptosis	[106]
	TLR4 depletion		Diminishes renal damage after Cisplatin induced AKI	[107]

Acronyms: AKI—acute kidney injury; AMPK—AMP (adenosine monophosphate)-activated protein kinase; ANG II—angiotensin II; Arid2-IR—AT-rich interactive domain 2-IR; BNIP3—BCL2 (B-cell lymphoma 2) interacting protein 3; Ca²⁺—calcium; CBP—CREB-binding protein; CDKIs—cyclin-dependent kinase inhibitors; CREB—cyclic adenosine monophosphate response element-binding protein; CRP—C-reactive protein; Erbb4-IR—erb-b2 receptor tyrosine kinase 4-IR; DCs—dendritic cells; DRP1—dynamin-related protein 1; EMT—epithelial to mesenchymal transition; ERK—extracellular-signal-regulated kinase; Exo/miR-29—exosome-encapsulated miR-29; FLT3—Fms-like tyrosine kinase 3; FMT—fibroblast to myofibroblast transition; Fn-14—fibroblast growth factor-inducible 14; GAS5—growth arrest specific-5; GC1—mitochondrial glutamate carrier-1; GPX4—glutathione peroxidase 4; GSK3β—glycogen synthase kinase 3β; HIF—hypoxia-inducible factor; IL—interleukin; IRI—ischemia-reperfusion injury; JAK—Janus kinase; MAP—mitogen-activated protein kinases; MAPK—mitogen-activated protein kinase; MLKL—mixed lineage kinase domain-like pseudokinase; MMP-7—matrix metalloproteinase-7; MMT—macrophage (bone marrow derived) myofibroblast transition; Mst1—macrophage-stimulating 1; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; NOX-D21—crystallographic structures of an active Spiegelmer; OPA1—a gene encoding a dynamin-like mitochondrial GTPase, involved in autosomal dominant optic atrophy; Orai1—calcium release-activated calcium channel protein 1; PAI—plasmin activator inhibitor; PARP1—poly (ADP-ribose) polymerase 1; PHD—prolyl hydroxylase domain; PINK1—PTEN-induced kinase 1; POU4F1—POU domain, class four, transcription factor 1; PTECs—proximal tubular epithelial cells; PTEN/Akt pathway—phosphatase and tensin homolog deleted on chromosome 10/protein kinase B pathway; ROS—reactive oxygen species; RIPK—receptor-interacting protein kinase; SAR131675—selective VEGF receptor-3 tyrosine kinase inhibitor; SET9—histone methyltransferase; SLE—systemic lupus erythematosus; SMA—smooth muscle actin; SMAD—acronym for the Caenorhabditis elegans SMA, “small” worm phenotype and MAD family, “mothers against decapentaplegic” of genes in Drosophila; Snail—gene encoded a nuclear protein similar to Drosophila embryonic protein snail; Src—sarcoma gene; TASCC—TOR (target of rapamycin)-autophagy spatial coupling compartment; TGF-β—transforming growth factor beta; TNF-α—tumor necrosis factor alpha; TLR—Toll-like receptor; TRPC6—transient receptor potential canonical 6; TWEAK—TNF-like weak inducer of apoptosis; UUO—unilateral ureteral obstruction; VDR—vitamin D receptor; VEGF—vascular endothelial growth factor; Wnt/β-catenin—wingless/β-catenin.