Molecular mechanism of nanomaterials induced liver injury: A review

Table 1 Effects and molecular mechanisms underlying SiO₂NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & Mechanism	Ref.
SiO2NPs	15 nm (TEM)	HepG2 cell	1-200 ug/mL for 72hrs.	Bcl-2, GSH, Cell viability (decreased); p53, Bax, caspase-3, ROS production, LPO (increased)	[85]
				Oxidative stress & Apoptosis
SiO2NPs	15 nm (TEM)	Kupffer cells from Sprague Dawley rats; Sprague Dawley rats	50, 100, 200, 400, and 800 μg/mL for 24 h. 50 mg/kg single (i.v.)	ROS, AST, LDH, TNFα, H2O2, NO (increased); Kupffer cells (activation); Infiltration of inflammatory cells	[80]
				Activated Kupffer cells-mediated inflammation in liver toxicity
SiO2NPs	30, 50, 70, 300, 1000 nm (TEM)	BALB/c male mice	10-40 mg/kg (i.v.)	ALT, AST (increased)	[75]
				Acute liver injury
Amorphous SiO2NPs	62.26nm (DLS)	HepG2	25, 50, 75, 100 μg/mL, 24 h	ROS levels; Autophagy and autophagic cell death via PI3K/Akt/mTOR pathway	[84]
				Oxidative stress
Amorphous SiO2NPs	aSiNP-189 (20nm), aSiNP-116 (50nm), aSiNP-26 (110nm), aSiNP-8 (250nm) (EM)	HepG2	10–200 μg/mL, 24 h	Cholesterol biosynthesis (increased); May affect steroidogenesis & bile formation	[19]
Amorphous SiO2NPs	19.8 ± 2.7 nm (TEM)	HL-7702 cells; BRL-3A cells	31.4–500 μg/mL, 72 h	p53, Bax, cleaved caspase-3 (increased); GSH levels, caspase-3, Bcl-2 (decrease); Activation of p53/casp-3/Bax/Bcl-2 pathway; Human cells are more sensitive than rat cell	[86]
				Oxidative stress & apoptosis
SiO2NPs	30 nm (TEM)	Mouse hepatocytes	500 μg/mL, 24 h	ALT, AST (increased); ALR (blockage); Enlarged autolysosomes	[82]
				Inflammation
Amorphous SiO2NPs	202.3 (DLS)	HepG2; ICR mice	50 mg/kg b.w. for 24 h (oral)	GSH, NADPH oxidase depletion; ROS (increased); Altered GSH metabolism	[77]
				Oxidative stress
SiO2NPs	10 nm (BET)	Albino Wistar rats	2 mg/kg daily 20, 35 or 50 injections (i.p.)	ALP, AST, ALT, LDH, procalcitonin, iron, phosphorus, potassium (increased); Phase I and II drug metabolizing and transporting enzymes (downregulation); Hydropic degeneration, karyopicnosis, Sinusoidal dialation, Kupffer cell hyperplasia, lowered liver index, infiltration of inflammatory cells	[79]
				Oxidative stress & Inflammation
SiO2NPs	15.4 ± 1.8 nm (TEM)	Kunming mice (normal & metabolic syndrome model)	10 mg/kg b.w. daily 30 d (oral)	Liver fibrosis (collagen deposition); Hepatic ballooning; DNA damage (genotoxicity) ROS production, mitochondrial damage, infiltration of inflammatory cells	[87]
				Mitochondrial instability & inflammation
Mesoporous SiO2NPs	109.2 (DLS)	L02 cells; BALB/c mice	5–120 μg/mL, 24 and 48 h; 50 mg/kg 3 times a week for 3 wk (i.v.)	ALT, AST, ROS (increased); NLRP3 inflammasome activation; Pyroptosis via caspase-1 activation	[78]
				Oxidative stress and inflammation
SiO2NPs	58 nm (TEM)	L-02 cells	6.25, 12.5, 25, 50, and 100 μg/mL) for 12 h and 24 h	ROS production; ER stress; Activation of EIF2AK3 and ATF6 pathway; Induction of autosome formation	[83]
				Oxidative stress
SiO2NPs	58.04 ± 7.41 (TEM)	L02 cells	12.5, 25, 50, 100 μg/mL, 24 h	Affect mitochondrial quality control (MQC) process, Mitochondrial fission (increased); Induced mitophagy via activated PINK/Parkin signaling pathway; Decreased mitochondrial biogenesis via PGC1α-NRF1-TFAM signaling pathway; Mitochondrial dysfuntion	[88]
				Mitochondrial dysfunction & oxidative stress
SiO2NPs	58.11 ± 7.30 nm (TEM)	Sprague dawley rats	1.8, 5.4, 16.2 mg/kg b.w. (i.t.)	ALT, AST, TG, LDL-C (increased) HDL-C (decreased); Impact on Purine, amino acids metabolism, glucose-alanine cycle	[81]
				Metabolic disorder
SiO2NPs	15nm (XRD)	Wistar rat	25 and 100 mg/kg b.w. for 28 consecutive days (i.p.)	AST, ALT, LDH, NO, MDA, PCO, H2O2, Bax, p53, Caspase-9/3 (increased)	[89]
				CAT, SOD, GPx, Bcl2 (decreased)
				Oxidative stress & apoptosis
SiO2NPs	59.98nm (TEM)	Free Fatty Acid treated – L-02 cells; ApoE-/- mice	1.5, 3, 6 mg/kg b.w once per week for 12 times (i.t.)	LDH, AST, ALT, MDA (increased); GSH/GSSG (decreased); Fatty acid synthesis (increased); β-oxidation(decreased); Disturbed amino acid & lipid metabolism; Lipid accumulation leads to ER stress; Downregulated Nrf2 signaling	[90]
				Oxidative stress, altered lipid metabolism

Akt: Protein kinase B; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ATF6: Activating transcription factor 6; Bax: Bcl-2 associated X protein; Bcl2: B-cell lymphoma 2; CAT: catalase; DNA: Deoxy ribonucleic acid; EIF2AK3: Eukaryotic translation initiation factor 2-alpha kinase 3; ER: Endoplasmic reticulum; GPx: Glutathione peroxidase; GSH: Glutathione; GSSG: Glutathione disulfide.H₂O₂-hydrogen peroxide; HDL-C: High-density lipoprotein; LDH: Lactate dehydrogenase; LDL-C: Low-density lipoprotein; LPO: Lipid peroxidation; MDA: Malondialdehyde; mTOR: Mammalian target of rapamycin; NADPH: Reduced nicotinamide dinucleotide phosphate; NLRP3: NOD-like receptor protein 3; GSH: Glutathione; NO: Nitric oxide; NRF1/Nrf2: Nuclear factor erythroid 2-related factor1/2; p53-tumor suppressor protein p53; PGC1α: Peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PI3K: Phosphatidylinositol 3-kinase; PINK: PTEN induced kinase, ROS: Reactive oxygen species, SOD: Superoxide dismutase; TFAM: Mitochondrial transcription factor A; TG: Triglyceride; TNFα: Tumor necrosis factor alpha.

Table 2 Effects and molecular mechanisms underlying NiONPs & NiNPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
NiO NPs	44 nm (TEM)	HepG2 cells	2-100 μg/mL for 24 h	Cell viability (reduced); ROS (increased); Micronuclei induction, chromatin condensation and DNA damage; bax and caspase-3 (upregulated); bcl-2 (downregulated)	[95]
				Oxidative stress, apoptosis
NiO NPs	20 nm (TEM)	Wistar rat	0.015, 0.06 or 0.24 mg/kg b.w. twice a week for 6 wk (i.t.)	NO, TNOS, iNOS, ·OH, LPO, HO1 (increased); CAT, GSHPx, T-SOD and TAOC, MT1 (decreased)	[93]
				Oxidative & nitrative stress
NiO NPs	20 nm (SEM)	Wistar rat	0.015, 0.06, and 0.24 mg/kg b.w. twice a week for 6 wk (i.t.)	GRP78, CHOP (increased); Activation of PERK/eIF-2α, IRE-1α/XBP-1S, and caspase-12/-9/-3 pathways	[16]
				ER stress, apoptosis
NiO NPs	20 nm (SEM)	Wistar rat	0.015, 0.06, and 0.24 mg/kg b.w. twice a week for 6 wk (i.t.)	ALT, AST, ALP, GGT, IL-1β and IL-6, TNF-α, NIK, IKK-α, NF-κB (increased); IL-4, IL-10, IκB(α) (decreased); Activation of NF-kB signalling pathway	[94]
				Inflammation
NiO NPs	13.16 ± 2.98 nm (TEM)	Wistar rat	125, 250 and 500 mg/kg single dose (oral)	ALP, LDH, ALT, AST, LPO (upregulation); GSH, SOD (downregulation)	[92]
				Oxidative stress
NiO NPs	21.6 ± 3.6 nm (TEM)	HepG2	5, 10, 25, 50 and 100 μg/mL, 24 h	HIF-1α, miR210, p53, Caspase-3, 8 and 9, NO, MMP (increased); Phagosome formation by lysosomal pathway	[96]
				Hypoxia & oxidative stress, apoptosis
NiO NPs	44 nm (TEM)	Wistar rat; HepG2	0.015, 0.06, and 0.24 mg/kg twice a week for 9 wk (i.t.); 25-200 μg/mL	TGF-β1, Smad2, Smad3, α-SMA, MMP9, TIMP1, EMT (upregulation); E-cadherin, Smad7 (downregulation); activation of TGF-β1/Smad pathway	[97]
				Hepatic fibrosis, ECM deposition
NiNPs	55.8 ± 14.0 nm (TEM)	C57/BL6 mice	10, 20 and 40 mg/kg/d for 7 and 28 d	ALT, AST, Ire1α, Perk and Atf6, TG increased; Lipid metabolism dysfunction; Inflammation	[98]
				ER stress, apoptosis

OH: Hydroxyl radical; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Atf6: Activating transcription factor 6; CAT: Catalase; CHOP: C/EBP Homologous Protein; ECM: Extra cellular matrix; eIF2α: Eukaryotic initiation factor 2 α; EMT: Epithelial mesenchymal transition; GGT: Gamma-glutamyl transpeptidase; GRP78: Glucose regulated protein 78; GSH: Glutathione; GSHPx: Glutathione peroxidase; HIF-1α: Hypoxia inducible factor 1; HO1: Heme oxygenase 1; IKK-α: IκB kinase alpha; IL-1β: Interleukin 1 β; IL-6: Interleukin 6; iNOS: Inducible nitric oxide synthase; IRE-1α: Inositol-requiring enzyme type 1α; IκB(α): Inhibitor kappa B alpha; LDH: Lactate dehydrogenase; LPO: Lipid peroxidation; miR210: miRNA210; MMP9: Matrix metallopeptidase 9; MMP: Mitochondrial membrane potential; MT1: Metallothionein 1; NF-κB: Nuclear factor kappa beta; NIK: NF-κB-inducible kinase; NO: Nitric oxide; p53-tumor protein p53; PERK: Protein kinase RNA like ER kinase; Smad2: Suppressor of mothers against decapentaplegic2; SOD: Superoxide dismutase; TAOC: Total antioxidative capacity; TG: Triglyceride; TGF-β1: Transforming growth factor 1 beta; TIMP1: TIMP metallopeptidase inhibitor 1; TNF-α: Tumor necrosis factor α; TNOS: Total nitric oxide synthase; TSOD: Total superoxide dismutase; XBP-1S: X box binding protein-1S; α-SMA: Alpha smooth muscle actin.

Table 3 Effects and molecular mechanisms underlying WO₃NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
WO3 NPs	60-70 nm, length WO3nanorods shorter (125−200 nm) and longer (0.8−2 μm)	BALB/c mice	2.5/5/10/20 mg/kg/d of shorter WO3 nanorods; 2.5/5/10/20 mg/kg/d longer WO3 nanorods for 14 d (i.p.)	ALT, AST; NF-κB, TNF-α, IFN-γ, IL-4 (increased); GSH, SOD (decreased)	[17]
				Oxidative stress, inflammation

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GSH: Glutathione; IFN-γ: Interferon gamma; IL-4: Interleukin 4; NF-κB: Nuclear factor kappa B; SOD: Superoxide dismutase; TNF-α: Tumor necrosis factor α.

Table 4 Effects and molecular mechanisms underlying CuONPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
CuO-NPs	33 nm (XRD)	Wister rats	300 mg/kg b.w. per day for 7 d (i.g.)	ALT, AST (increased)	[18]
CuO- NPs	40 nm (TEM)	Mature rats (Rattus norvegicus var. albinos)	0.5, 5, and 50 mg/kg b.w./d for 14 d (oral)	CAT, GPx, GR (increased) GST (decreased)	[100]
CuO-NPs	BNPs 4.14-12.82 nm CNPs 4.06-26.82 nm (XRD)	Mature mice	500 mg/kg b.w. single dose (oral)	ALT, AST, P53, Caspase - 3 (increased); Hepatic necrosis	[101]
Nano-CuO	20-40 μm (TEM)	BRL-3A cells; Wister rat	5, 10, 20 μg/mL; 10 μg/g b.w. for 60 d (i.n.)	ALT, AST, T-BIL, D-BIL, I-BIL (increased) ALP (decreased); SOD (decreased); MDA, iNOS, GSH-PX (increased); MCP-1, IL-1, IL-1β, TNF-α, IL-6 (increased); JNK, PERK, CHOP, ATF4, eIF2α, IRE1, Calpain, GRP78, ATF6, Bax, Caspase-3, Caspase-12 (upregulated)	[102]
				Oxidative stress induced ER stresspathway activation
CuO-NPs	GNPs & CNPs	Sprague dawley rat	50 & 100 mg/kg b.w. twice a week starting before mating (oral)	CAT, GSH, GPx (decreased)	[103]
CuO-NPs	< 50 nm (TEM)	Wistar rat	5 mg, 10 mg, 25 mg/kg b.w. per day for 9 d (i.p.)	Mild to severe Liver tissue damage including necrosis of hepatocyte, anti-inflammatory cell infiltration	[104]

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ATF4/6: Activating transcription factor4/6; Bax: Bcl-2 associated X protein; CAT: Catalase; CHOP: C/EBP Homologous Protein; D-BIL: Direct bilirubin; eIF2α: Eukaryotic initiation factor 2 α; BNP: Biologically synthesized nanoparticle; CNP: Chemically synthesized nanoparticle; GNP: Green nanoparticle; ER: Endoplasmic reticulum; GPx: Glutathione peroxidase; GR: Glutathione reductase; grp78: Glucose regulated protein 78; GSH: Glutathione; GSH-PX: Glutathione peroxidase; GST: Glutathione-S-transferase; I-BIL: Indirect bilirubin; IL-1: Interleukin 1; IL-1β: Interleukin 1 β, IL-6: Interleukin 6; iNOS: Inducible nitric oxide synthase; IRE-1: Inositol-requiring enzyme type 1; JNK: Jun N-terminal kinase; MCP-1: Monocyte chemoattractant protein 1; MDA: Malondialdehyde; P⁵³: Tumor protein p53; PERK: Protein kinase RNA like ER kinase; SOD: Superoxide dismutase; T-BIL: Total bilirubin; TNF-α: Tumor necrosis factor α.

Table 5 Effects and molecular mechanisms underlying ZnONPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
ZnO NPs	Micro size; Nano size 63 nm (SEM)	Sprague Dawley rat	5, 50, 300, 100, 2000 mg/kg b.w for 14 d (oral)	AST, ALT (increased)	[20]
ZnO NPs	35 nm (TEM)	Wistar albino rats	2 mg/kg b.w. for 21; Days (i.p.)	Histopathological alterations; Kupffer cell activation	[106]
				Inflammation
ZnO NPs	50 nm (TEM)	Wistar albino rats	600 mg/kg/b.w and 1 g/kg/b.w for 5 d	ALT, NO, TNF-α, IL-6, CRP, IgG (increased)	[107]
				Inflammation
ZnO NPs	80 nm (TEM)	C57BL/6 mice	200 mg/kg/d (low dose) and 400 mg/kg/d (high dose) for 90 d (oral)	ALT, AST (increased); grp78, grp94, pdi-3, xbp-1(increased ER stress related proteins); Increased phosphorylation of PERK & eIF2α; caspase-3, 9, 12 (apoptosis); phosphorylation of JNK, and CHOP/GADD153; upregulation of Chop, Bax	[105]
				ERstress mediated activation of apoptotic pathway
ZnO NPs	30 nm (TEM)	HepG2 cell	14–20 μg/mL for 12 h	AST, ALT, Bax (increased) Bcl2 (decreased) LDH leakage; JNK, P38 activation	[108]
				Apoptosis
ZnO NPs	Less than 15 nm (TEM)	Sprague dawley albino rats	100, 200, 300 mg/kg b.w. per day for 14 d (oral)	ALT, AST, ALP (increased); Bax, caspase-3 (increased); Bcl2 (decreased); Modulation of JNK/p38MAPK & STAT-3 signalling pathways	[109]
				Apoptosis
ZnO NPs	20-50 nm (TEM)	HepG2 cells; sprague dawley rat	20 μg/mL for 24 h; 25 mg/kg b.w. for 7 d (i.p.)	Cell inactivation; Intracellular calcium overload; Mitochondrial damage	[110]
				Oxidative stress

ALP: Alkaline phosphatase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, Bax: Bcl-2 associated X protein, Bcl2: B-cell lymphoma 2, CHOP: C/EBP Homologous Protein, CRP: C reactive protein, IgG: Immunoglobulin G, eIF2α: Eukaryotic initiation factor 2 α, GADD153: Growth arrest and DNA damage 153, Grp 78/94: Glucose regulated protein 78/94, IgG: Immunoglobulin G, IL-6: interleukin 6, JNK: Jun N-terminal kinase, LDH: Lactate dehydrogenase, MAPK: Mitogen activated protein kinase, NO: Nitric oxide, p38: Protein kinase, pdi-3: Protein disulfide isomerase -3, PERK: Protein kinase RNA like ER kinase, STAT-3: Signal transducer and activator of transcription 3, TNF-α: Tumor necrosis factor α, IL-6: Interleukin 6; xbp-1: X box binding protein-1.

Table 6 Effects and molecular mechanisms underlying TiO₂NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
TiO2NPs (Anatase)	7 nm (XRD)	80 CD-1 (ICR) mice	5, 10, 50 mg/kg b.w. every other day for 60 d (i.g.)	SOD, CAT, GSH-Px, MT, HSP70, GST (downregulation); CYP1A (upregulation)	[117]
				Oxidative stress, apoptosis
TiO2NPs (Anatase)	5 nm (XRD)	CD-1 (ICR) mice	5, 10, 50, 100, 150 mg/kg b.w. daily for 14 d (abdominal injection)	Accumulated in liver DNA; Inserted in DNA base pairs; Binds to DNA nucleotides; Alter DNA secondary structure; Liver DNA cleavage at higher dose	[119]
				Genotoxicity
TiO2NPs	< 25 nm anatase; < 100 nm rutile (SEM)	HepG2 cell	1, 10, 100 and 250 mg/mL incubated for 4, 24, 48 h	p21, mdm2, p53, gadd45α (increased expression); DNA strand break; DNA damage; ROS production	[120]
				Genotoxicity
TiO2NPs (Anatase)	5 nm (XRD)	80 CD-1 (ICR) mice	5, 10, 50 mg/kg b.w. for 60 d (i.g.)	TLR2, TLR4, IKK1, IKK2, NF-kB, NF-kBP52, NF-kBP65, TNF-α, NIK (upregulation); IkB, IL-2 (downregulation); ALT, AST, ALP, LDH, PCh, LAP (upregulation)	[116]
				Inflammation, apoptosis
TiO2NPs (Anatase & rutile)	Anatase –561.63 ± 26.26 nm; Rutile – 206.22 ± 2.18 nm (TEM)	HepG2 cell	5-320 μg/mL for 24 h	ERK1/2, p38 (increased phosphorylation); TNFα (upregulated); A20 (downregulated); Activation of MAPK & NF-kB pathway	[115]
				Inflammation
TiO2NPs; Rutile anatase; P25 (anatase: rutile = 75:25)	Rutile – 50 nm; Anatase – 50 nm; P25 – 21 nm (TEM)	Primary hepatocytes of Sprague Dawley rats	50 μg/mL, 72 h	ROS (upregulated); Urea, albumin, MnSOD, MMP, Mfn 1, Opa 1 (downregulated)	[122]
				Perturbation of mitochondrial dynamics, oxidative stress
TiO2NPs; Rutile	12-18 nm (TEM)	BRL 3A cells; sprague dawley rats	0.1-100 μg/mL for 6 h; 0.5-50 mg/kg BW intraperitoneal injection 24 h	Rapid G0/G1 to S transition, G2/M arrest; ALT, AST, ALP, LDH (upregulated)	[123]
				Hepatocytes with oxidative stress show more cytotoxicity
TiO2NPs; Anatase	10 (TEM)	B6C3F1 mice	50 mg/kg b.w. daily for 3 d (i.p.)	DNA strand break nucleotide oxidization; MT1H, MT1E (upregulation); Differential gene expression(increased)	[121]
				Oxidative stress, Genotoxicity, metabolic imbalance
TiO2NPs; Anatase	19 (XRD)	Wistar rat	100 mg/kg daily for 60 d (oral)	ALT, AST, ALP, LPO (increased); GSH, SOD, GPx, CAT (decreased); vacuolization, Sinusoidal dilation, inflammatory cells infiltration	[124]
				Oxidative stress
TiO2NPs; Anatase	10 nm (TEM)	Albino rats	100 mg/kg daily	ALT, AST, ALP, Bax, LPO (increased); GPx, SOD, GSH, Bcl-2, (decreased); hepatic apoptosis; Sinusoidal dilation, infiltration inflammatory cells, steatosis, hepatocellular necrosis	[125]
			60 d (oral)	Oxidative stress
TiO2NPs; anatase: Rutile (80: 20)	20 nm (TEM)	Wistar rat	300 mg/kg daily for 2 wk (oral)	ALT, AST, ALP, LDH, TNFα, NF-Kβ, TOS, LPO (upregulated); SOD, CAT, GPx, TAC (downregulated)	[118]
				Inflammation, Oxidative stress
TiO2NPs; Anatase	29 ± 9 nm (SEM)	Sprague dawley rats	2, 10, 50 mg/kg b.w. daily for 90 d (oral)	LPO, GPx, SOD, GSSG, IL-1α, IL-4 and TNFα (increased); GSH (decreased); Mitochondrial swelling increased gut microbiota altered glycerophospholipid, Phosphatidylcholines metabolism; Hepatotoxicity indirectly through gut liver axis	[126,127]
				Oxidative stress, inflammation

A20: Alpha-induced protein-3; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Bax: Bcl-2 associated X protein; Bcl2: B-cell lymphoma 2; CAT: Catalase; CYP1A: Cytochrome p450 1A; DNA: Deoxy ribonucleic acid; ERK1/2: Extracellular signal-regulated protein kinases 1 and 2; gadd45α: Growth arrest and DNA damage 45 alpha; GPx/GSH-Px: Glutathione peroxidase; GSH: Glutathione; GSSG: Glutathione disulfide; GST: Glutathione S transferase; HSP70: Heat shock protein 70; IkB: Inhibitor kappa B; IKK1,2: IκB kinase; IL-1α: Interleukin 1 alpha; IL-2,4: Interleukin-2,4; LAP: Leucine acid peptide; LDH: Lactate dehydrogenase; LPO: Lipid peroxidation; MAPK: Mitogen activated protein kinase; mdm2: Murine double minute 2; Mfn 1: Mitofusin 1; MMP: Mitochondrial membrane potential; MnSOD: Manganese superoxide dismutase; MT: Metallothionein; MTIE: Metallothionein 1E; MTIH: Metallothionein 1H; NF-kB: Nuclear factor kappa beta; NIK: NF-κB-inducible kinase; Opa 1: Optic atrophy 1; p21: Cyclin-dependent kinase inhibitor 1; p38: Puncture38; p53: Tumor suppressor protein p53; PCh: Pseudocholinesterase; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TLR2/4: Toll like receptor 2/4; TNF-α: Tumor necrosis factor α; TOS: Total oxidant status.

Table 7 Effects and molecular mechanisms underlying MgONPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
MgO	-	3D Human Liver organoids male Sprauge Dawley rat	100 μg/mL incubated for 48 h. 40 mg/kg daily for 4 wk (oral)	ATP synthesis (decreased); ROS & Super oxide production (increased); ALT, AST (increased)	[21]
				Oxidative stress

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ATP: Adenosine triphosphate; ROS: Reactive oxygen species.

Table 8 Effects and molecular mechanisms underlying Al₂O₃NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Al2O3	< 50 nm	Developing chicken embryo, HepG2 cell culture model	10, 20, 40 μg/egg via injection from 8th to 12th day of incubation on an alternate day basis, 05, 10, 20 μg/mL for 12 h	ROS & Super oxide production (increased); ALP, ALT, AST activity (increased); HO-1, NQO-1 level (increased); Cell viability (decreased); SOD, CAT, GPx, TBARS, TNF-α, Caspase-3 activity (decreased)	[128]
				Oxidative stress and cytotoxicity

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HO-1: Heme oxygenase-1; NQO-1: NAD(P)H quinone oxidoreductase 1; SOD: Superoxide dismutase; CAT: Catalase; GPx: Glutathione peroxidase; TBARS: Thiobarbituric acid reactive substances; TNF-α: Tumor necrosis factor α; ROS: Reactive oxygen species.

Table 9 Effects and molecular mechanisms underlying Cr₂O₃NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Cr2O3-NPs	22.50 + 1.76 nm (TEM)	Wistar rats	50 mg/100 g bwt (LD), 200 mg/100 g bwt (HD); single dose for 1, 7, 14 d (oral)	ALT, AST, ALP, γGT, total bilirubin (increased)	[23]

ALP: Alanine phosphatase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, HD: High dose, LD: Low dose, γGT: Gamma glutamyltransferas.

Table 10 Effects and molecular mechanisms underlying iron oxide NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Na-oleate coated Fe3O4	8 ± 3 nm (TEM)	Wistar rat	0.0364, 0.364, & 3.64 mg/kg b.w. for 1 d, 1, 2, 4 wks (i.v.)	Temporary change in mitochondrial respiration; GPx, GST (increased); Lipidosis, mild necrosis; Enlarged sinusoid space	[133]
				Oxidative stress
Polyethylene glycol – 8000 coated Fe3O4	8.82 ± 0.70 nm (TEM)	Wistar rat	10 mg/kg b.w. single dose, once in a week, twice in a week for 30 d (i.v.)	ALT, AST, ALP (slightly increased); AST, LPO, SOD, GPx, Neutrophil count (increased); No significant tissue damage	[135]
Fe3O4	20 nm (TEM)	Wistar rat	40 mg/kg b.w. for 14 d (i.t.)	Congestion of sinusoid; Hepatocytic ballooning; Mononuclear cell infiltration; Tissue damage	[132]
				Inflammation
Fe3O4	41.3 ± 5.9 nm for USPIO, 112.6 ± 38.4 nm for SPIO (DLS)	L-02 cells	2.5, 5, 10, and 20 μg/mL) for 12 h	Cell survivility (decreased); Elevated expression of Genes related to acute phase inflammation, ER stress. HSP70, IL-6, PERK, ATF4, ER Ca++ (increased); USPIO show higher toxicity than SPIO	[136]
				ER stress, inflammation
Fe3O4	10 nm (TEM)	Hepatocytes of Lewis rat in sandwich culture model	100, 200, 400 μg/mL, single dose & cumulative dose; 24 h to 7 d	Cell survivility (decreased); ROS (increased); Albumin & urea synthsis (decreased)	[134]
				Oxidative stress
Fe3O4	29.6 ± 12.2 nm (TEM)	Albino wistar rat	30, 300, 1000 mg/kg b.w. for 28 d (nano & bulk) (oral)	GSH, CAT (decreased); SOD, GR, GST, LPO (increased); GPx (unchanged); Congested central vein in higher dose	[130]
				Oxidative stress
Fe2O3	30 nm (TEM)	Wistar rat	100, 200 mg/kg single dose (oral)	ALT (increased) iron deposition in hepatocyte & Kupffer cells	[131]
				Inflammation
Fe2O3	30 nm (TEM)	L-02 cells; BALB/C mice	2.5, 7.5, and 12.5 lg/mL) for 1, 3, 6 h; 20 mg/kg body weight for 24 h. (i.v.)	Cox2 (overexpression); COX-2 interaction with IP3R-GRP75-VDAC1 complex; Ca++ transfer increased; Bax, Cleaved Casp-3 (increased); Bcl2 (decreased)	[137]
				Apoptosis

ALP: Alanine phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Atf4: Activating transcription factor 4; Bax: Bcl-2 associated X protein; Bcl2: B-cell lymphoma 2; Ca++: Calcium ion; CAT: Catalase; COX-2: Cyclooxygenase-2; ER: Endoplasmic reticulum; GPx: Glutathione peroxidase; GR: Glutathione reductase; GRP75: Glucose regulated protein 75; GSH: Glutathione; GST: Glutathione S-transferase; HD: High dose; HSP-70: Heat shock protein 70; IL-6: Interleukin-6; IP3R: Inositol 1,4,5 triphosphate receptor; LD: Low dose; LPO: Lipid peroxidation; PERK: Protein kinase RNA like ER kinase; ROS: Reactive oxygen species; SOD: Super oxide dismutase; SPIO: Superparamagnetic iron oxide; USPIO: Ultra-small superparamagnetic iron oxide; VDAC1: Voltage-dependent anion channel 1; γGT: Gamma glutamyl transferase.

Table 11 Effects and molecular mechanisms underlying GONPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
GO	100-500 nm (TEM)	Sprague dawley rats	2.5, 5, and 10 mg/kg/d for 7 d (i.v.)	Liver inflammation; Cholesterol, HDL, LDL (decreased)	[144]
GO	40 nm (TEM)	Sprague Dawley rats	10, 20 and 40 mg/Kg b.w. once for 5 d, (oral)	ROS, AST, ALT, LHP (increased)	[146]
GO	0.8-2 nm (TEM)	Wistar rats	0.4/2/10 mg/kg b.w.	AST, ALP, ALT, MDA (increased); CAT (decreased)	[147]

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CAT: Catalase; HDL: High density lipoprotein; LDL: Low density lipoprotein; LHP: Lipid hydro peroxide; MDA: Malondialdehyde; ROS: Reactive oxygen species.

Table 12 Effects and molecular mechanisms underlying carbon nanotube induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
MWCNTs	O-MWCNT; T-MWCNT; Length 356 ± 185 nm	Kunming mice	10 and 60 mg/kg b.w. (Iv) sacrificed at 15 & 60 d	GSH, SOD (decreased at 15 days); AST, T-Bil (increased); Spotty necrosis, Infiltration of inflammatory cells in portal region, mitochondrial swelling and lysis; Cyp2B19 (upregulated); Cyp2C50, Gsta2 (downregulated)	[149]
				Oxidative stress, Inflammation
PEGylated; MWCNT	P- MWCNT; NP- MWCNT; Length of less than 1 μm; Diameter of 10-20 nm	Kunming mice	10 and 60 mg/kg b.w. (Iv) sacrificed at 15 & 60 d	Blackish discoloration of the liver (MWCNTs accumulation); AST, Bag4, Gab1 genes (increased); Infiltration inflammatory cells, cellular necrosis, focal necrosis; Mitochondrial swelling/lysis; NP- MWCNT shows more toxicity than P- MWCNT	[155]
				Inflammation
Carboxylated functionalized SWCNT	lengths of 15–20 μm; Diameter of 15–30 nm	Swiss webster mice	0.25, 0.5 & 0.75 mg/kg b.w. per day for 5 d (Ip)	ROS, LHP, ALT, AST, ALP, (increased); Histological alterations	[153]
				Oxidative stress
Carboxylated functionalized; MWCNTs	lengths of 15–20 μm; Diameter of 15–30 nm	Swiss webster mice	0.25, 0.5 & 0.75 mg/kg b.w. per day for 5 d (Ip)	ROS, LHP, ALT, AST, ALP, (increased); Histological alterations	[154]
				Oxidative stress
MWCNTs	Length 5-50 μm; Diameter 20-30 nm (SEM)	Swiss albino mice	10 and 60 mg/kg b.w. (oral) sacrificed at 7, 14, 21, 28 d	SOD, CAT activity (decreased); Macrophage injury, cellular swelling, unspecific inflammation, spot necrosis, blood coagulation. The sinusoid and hepaticvenule diameter increased by the high dose	[156]
				Oxidative stress
SWCNTs	Length several μm; Diameter 0.8-1.2 nm (TEM)	Wistar rat	7.5 (low), 15 (medium), and 22.5 (high) mg/kg b. w. Intratracheal instillation once for 15 d	ALB, ALP, TP, TC (decreased at high conc.); Focal necrosis, inflammatory cell infiltration, Cellular swelling at centrilobular part, membrane fluidity destruction, impaired amino acid & lipid metabolism	[150]
				Metabolic disruption, Hepatotoxicity
Oxidised MWCNTs	Length 1-2 μm; Diameter 10-30 nm (TEM)	Kunming mice (Cd-MT accumulated mice)	500 μg/mouse for 4 h	ALT, AST, TBil, BUN (increased); Released Cd++ from Cd-MT; Adsorb a part of free Cd++	[157]
				Coexpossure ameliorated hepatotoxicity
Carboxylated MWCNTs	Length 12 μm; Diameter 11.5 nm (TEM)	Wistar rat	0.25, 0.50, 0.75 and 1.0 mg/kg b.w. for 5 consecutive days (Ip)	ALT, AST, ALP, GGT (increased); LPO, H2O2, CAT, GPx, activity (increased); SOD, GST (decreased); IL-6, IL-1β, COX-1, iNOS, TNF-α (increased); micronucleated polychromatic erythrocytes (MNPCE)	[151]
				Oxidative stress, Inflammation
MWCNTs	Polycrystalline; Length 600-700 nm; Size 650 nm	Albino rat	1 g/kg b. w. (oral) 4 wk	LPO, H2O2, TT, CATactivity (increased); SOD, GSH, GPx, GST (decreased); IL-6, IL-1β, COX-1, TNF-α (increased); hydropic degeneration focal hepatic & perivascular hepatic necrosis associated with inflammatory cells, infiltration, sinusoidal leukocytosis, vacuolar degeneration, congestion of central vein	[4]
				Oxidative stress, Inflammation
Carboxylated MWCNTs	diameter: 5–15 nm, length: 0.5-2 μm (TEM)	C57BL/6J mice (NAFLD)	MWCNT; LD-10 mg/kg b.w. HD-30 mg/kg b.w. PbAc LD-150 mg/kg b.w. HD-300 mg/kg b.w. MWCNT+ PbAc, LD-10 mg/kg +150 mg/kg HD-30 mg/kg +300 mg/kg (Intragastrically) daily for 80 d	Death at high dose on 5th day. ALT, AST, ALP (decreased); Nonalcoholic steatohepatitis lobular inflammation, hepatic fibrosis, steatosis, apoptotic induction in primary hepatocytes of NAFLD mice; SOD, GST, GSH (decreased); H2O2, GPx, MDA, LPO (increased); Lipid peroxidation; IL-6, IL-1β and TNF-α (inflammatory cytokines) inhibiting AMPK/PPARγ pathway	[152]
				Oxidative stress, Inflammation

ALB: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AMPK: AMP activated protein kinase; AST: Aspartate aminotransferase; Bag4: BAG cochaperone 4; BUN: Blood urea nitrogen; CAT: Catalase; COX-1,2: Cyclooxygenase-1,2; Cyp2B19: Cytochrome P4502B19; Cyp2C50: Cytochrome P4502C50; Gab1: GRB2 associated binding protein 1; GGT: Gamma glutamyl transferase; GPx: Glutathione peroxidase; GSH: Glutathione; Gsta2: Glutathione S-transferase, alpha2; GST: Glutathione-S transferase; H₂O₂: Hydrogen peroxide; IL-1β: Interleukin-1beta; IL-6: Interleukin-6; iNOS: Inducible nitric oxide synthase; LHP: Lipid hydroperoxide; LPO: Lipid peroxidation; MDA: Malondialdehyde; NAFLD: Non-alcoholic fatty liver disease; O-MWCNT-acid: Oxidized multi-walled CNTs; PPARγ: Peroxisome proliferator-activated receptor-γ; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TBil: Total bilirubin; TC: Total cholesterol; T-MWCNT: Tween-80-dispersed multi-walled CNTs; TNF-α: Tumor necrosis factor alpha; TP: Total protein; TT: Total thiol.

Table 13 Effects and molecular mechanisms underlying CuS/CdS-NPs induced hepatonanotoxicit

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
CdS NPs	5-9 nm (TEM)	Wistar rat	10 mg/kg alternate days for 45 d	Hepatosomatic index (decreased); ALT, AST, ALP, LPO, H2O2, NO (increased); GSH (depletion); Cytoplasmic degeneration/coagulation, sinusoidal inflammation, parenchymal degeneratin, mitochondria, peroxisome, microsomes increased in number	[159]
				Oxidative stress
CuS/CdS	8.7 nm	hepatoma cells BEL7402 and L-02 normal liver cells; Balb/c mice	4 mg/kg, i,v injection	SOD, GSH (down regulation); ROS, GSSG, MDA (up regulation)	[158]
				Oxidative stress
Cu2-xS	17.8 nm (LNPs); 2.8 nm (SNPs)	Sprague Dawley rats	5 mg/kg through tail vein single dose	ALT, AST, TBA, LDH (increased) ALB (decreased)	[161]

ALB: Albumin, ALP: Alkaline phosphatase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, GSH: Glutathione, GSSG: Glutathione disulfid, H₂O₂: Hydrogen peroxide, LDH: Lactate dehydrogenase, LPO: Lipid peroxidation, MDA: Malondialdehyde, NO: Nitric oxide, ROS: Reactive oxygen species, SOD: Superoxide dismutase, TBA: Total bile acid.

Table 14 Effects and molecular mechanisms underlying cobalt NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Nano-Co	10-40 nm	Normal human liver L02 cells	2.5, 5, 7.5, 10, 20, and 40 μg/mL) for 12 h or 24 h	Modulation of ROS/NLRP3 pathway	[162]

NLRP3: NOD-like receptor protein 3; ROS: Reactive oxygen species.

Table 15 Effects and molecular mechanisms underlying nanoclay, NCD, polystyrene, chytosan induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Nano-Clay	57.8 ± 12.3 nm & 648.3 ± 232.2 nm	BALB/C mice	1, 5, 10, 20 mg/kg b.w. (Iv) 24 h; Co-administered with Ccl4, paraquat, cisplatin	ALT, AST (increased)	[163]
NCD (modified nanocellulose with oxalate esters)	100 nm (SEM)	Wistar rat	50 & 100 mg/kg b.w. (oral) for 7 d	ALT, AST (increased); CAT, GPx activity (decreased); MPO activity (increased); iNOS, Bax (increased); dialated sinusoidal space, vacuolated hepatocytes, cellular infiltration	[29]
				Oxidative stress
Polystyrene	PS NPs 158.8 ± 1.3 nm; aPS NPs 117.0 ± 1.8 nm (SEM)	ICR mice	50 mg/kg/d (oral) for 7 d	Glucose, HDL-C, TG, TC (increased in blood); LDL-C (decreased in blood); Activation of PI3K/AKT/GLUT4 & SREBP-1/PPARγ/ATGL signaling pathways; TG decomposition; Lipid accumulation (increased); Nuclear pyknosis, blurred intercellular space, central hepatic vein congestion, hepatic ballooning; Compared to PS NPs, aPS NPs showed higher toxicity	[28]
				Disruption of glycolipid metabolism
Chitosan (CsNPs)	18 ± 1 nm (DLS)	BHAL cell	≥ 0.5% w/v for 4 h	Readily internalized; Disrupt membrane integrity; ALT leakage; CYP3A4 enzyme activity (increased); necrotic or autophagic cell death	[27]

ALT: Alanine aminotransferase, aPS: UV aging Polystyrene, AST: Aspartate aminotransferase, ATGL: Adipose triglyceride lipase, Bax: Bcl-2 associated X protein, CAT: Catalase, CYP3A4: Cytochrome P4503A4, GLUT4: Glucose transporter 4, GPx: Glutathione peroxidase, HDL-C: High-density lipoprotein, iNOS: Inducible nitric oxide synthase, LDL-C: Low-density lipoprotein, MPO: Myeloperoxidase, NLRP3: NOD-like receptor protein 3, p-AKT: Phosphoprotein kinase B, PI3K: Phosphatidylinositol 3-kinase, PPARγ: Peroxisome proliferator-activated receptor-γ, PS: Polystyrene, ROS: Reactive oxygen species, SREBP-1: Sterol regulatory element binding protein-1, TC: Total cholesterol, TG: Triglyceride.

Table 16 Effects and molecular mechanisms underlying hydroxyapatite nanoparticles induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Hydroxyapatite nanoparticles	50 nm (XRD)	HepG2 cells; L-02 cells	100 μg/mL for 24, 48 h	Caspase-3, 9 (activated); Bax, Bid (upregulated); Bcl-2 (downregulated); Cytosolic appearance of cytochrome c	[164]
				Apoptosis
Hydroxyapatite nanoparticles	80 nm (TEM)	BRL cells; Sprague–Dawley rat	25, 50, 100, 200, 400 and 800 μg/mL for 1 h; 50 mg/kg (Iv) single dose, sacrificed at 48 h	Decreased cell viability; Increased LDH leakage; Induced apoptosis & necrosis; MAPK signaling pathway activation; WBC count, ALT, AST, TNF-α, H2O2, MDA (increased); Infiltration of inflammatory cells near portal area	[165]
				Oxidative stress, inflammation, apoptosis, necrosis

ALT: Alkaline phosphatase; AST: Aspartate aminotransferase; Bax: Bcl-2 associated X protein; Bcl2: B-cell lymphoma 2; Bid: BH3 interacting-domain death agonist; H₂O₂: Hydrogen peroxide; LDH: Lactate dehydrogenase; MAPK: Mitogen activated protein kinase; MDA: Malondialdehyde; TNF-α: Tumor necrosis factor alpha.

Table 17 Effects and molecular mechanisms underlying quantum dots induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
Cd/Se/Te QD705	12.3 ± 5.2 nm (TEM)	ICR mice	100 μL of 40 and 160 pmol (IV) sacrificed at 12 and 16 wk	ALT, AST (increased); GPx, HO-1, 8-oxo-dG (increased); Cu/Zn/Se (increased); SOD activity (decreased); GSH/GSSG; Unbalanced antioxidation systems; Trace metals, trace metal transporters; TNFα, IL-6 (increased)	[167]
				Oxidative stress and inflammation
CdSe QD	4 nm (TEM)	Kunming mice Hepa 1–6 cells	200 nMCdCl2, 20 nM & 200 nM QDs (acute) for 48 h (IP); 20 nMCdCl2, 5 nM & 10 nM QDs for 6 wk (chronic) (IP); 20 nM CdCl2, 5 nM, 10 nM and 20 nM QDs for 24 & 48 h	ROS, MDA (increased); GSH-Px (decreased); Enlarged central vein, disordered hepatic cords; Reduced cell size, condensation; Round and condensed macrophage	[166]
				Oxidative stress
Mn-doped ZnS QDs	3.8 ± 0.1 nm (TEM)	Kunming mice	1 & 5 mg/kg (QDs); 5 mg/kg (QDs PEG) (IV) for 7 da sacrificed on 8th & 28th day	QDs accumulated in mitichondia, lysosome, lipid droplets; No hepatic damage	[169]
CdTe QDs	2.2 nm (TEM)	AML 12; ICR mice	27.66, 41.49, 53.94, 70.12, 91.16 & 118.50 μg/mL for 24 & 48 h. 4.125, 8.25 and 16.5 mg/kg body weight (IV) once a week for 4 wk	LPO, MDA, SOD, CAT, P53, Bcl-2, Nrf2, HO-1 (increased); Bax (decreased); ATP concentration (decreased); Nrf2 signaling pathway activation	[170]
				Oxidative stress, apoptosis
CdTe QDs	7.3 ± 1.2 nm (TEM)	HepG2 cell	10 μg/mL containing 1 μg/mL of cadmium for 24 h	MMP disruption, mitochondrial swelling, increased intracellular ca2+ levels, impaired cellular respiration & decreased ATP synthesis; PGC-1α (increased)	[171]
				Mitochondrial toxicity & dysfunction
CdTe QDs	15.25 ± 0.34 nm (TEM)	BALB/c mice	0.4, 2, 5, 6, 7, and 10 mg/kg b.w (Iv) for 24 h; 5 mg/kg bw (Iv) 2 h, 24 h, 3 d, and 1 wk	Enlarged mitochondria with increment in number; Affects ETC complex & ATP synthesis energy metabolism impairment	[172]
				Mitochondrial dysfunction
CdSe/Zn-QD	7.1 nm (TEM)	L02 cells; C57BL/6 mice; NLRP3 knockout mice	5, 10, 20, 40, 80 nM, 24 and 48 h; 10 nmol/kg (IV) results at 2 wk	Dose-dependent decrease in cell viability pyroptosis; Caspase-1 activity(increased); NLRP3 inflammasome activation; mt ROS production (increased); Cytoplasmic Ca2+ (increased) levels ALT, AST, MPO, TNFα, IL-1β (increased); γ-GT (decreased)	[168]
				Oxidative stress and inflammation
Cd free indium -based QDs	4 nm (TEM)	Lister Hooded rats	12.5 & 50 mg/kg b.w. (Iv) for 24 h. 1 wk, 4 wk	ALT, AST, ALP (slightly increased); No hepatic damage	[25]
CdTe/CdS QDs	12 nm (TEM)	HL-7702; HepG2 cells	1- 32 nM for 48 h	Lysosomal internalization; Abnormal activation of lysosomal enzymes; ROS generation (increased); Autophagy	[3]
				Apoptosis independent nanotoxicity
CdTe QDs	15.25 ± 0.34 nm (TEM)	BALB/c mice	0.4, 2, 5, 6, 7, and 10 mg/kg b.w (Iv) for 24 h. 5 mg/kg b.w. (Iv)2 h, 24 h, 3 d (d), and 1 wk (w)	AST, ALT, T-bil (increased); Albumin (decreased); liver accumulation	[173]
CdTe QDs	15.25 ± 0.34 nm (TEM)	BALB/c mice	0.4, 2, 5, 6, 7, and 10 mg/kg b.w (Iv) for 24 h. 5 mg/kg b.w. (Iv) 2 h, 24 h, 3 d (d), and 1 wk (w)	tGSH, ATP (depletion) GST, CAT (decreased) SOD activity (increased); Hmox I, Ncf-1, Ncf-2 (upregulated expression); PGC-1α (increased)	[9]
				Oxidative stress, apoptosis
CdTe QDs	2.2-3.0 nm (TEM)	ICR mice; KUP5 cells	2.5 & 10 μM/kg· b.w. (Iv) single dose once per wekk for 14 d; 5, 50 & 500 NM	IL-1β, TNF-α, IL-6 (increased); Assembly of NLRP3 inflammasome; ROS productin (increased); Activation of NF-KB pathway; Kupffer cell activation	[174]
				Oxidative stress, Inflammation

8-oxo-dG: 8-oxo-7,8-dihydro-2¢-deoxyguanosine; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, ATP: Adenosine triphosphate; Bax: Bcl-2 associated X protein; Bcl-2: B-cell lymphoma 2; CAT: Catalase; Cu-copper; ETC: Electron transport chain; GSH-Px: Glutathione peroxidase; GSSG: Glutathione disulfide; GST: Glutathione S-transferase; HO-1/Hmox I: Heme oxygenase 1; IL-1β: Interleukin 1 β; IL-6: Interleukin-6; LPO: Lipid peroxidation; MDA: Malondialdehyde; MMP: Mitochondrial membrane potential; MPO: Myeloperoxidase; Ncf-1,2: Neutrophil cytosolic factor 1,2; NF-κB: Nuclear factor kappa beta; NLRP3: NOD-like receptor protein 3; Nrf2: Nuclear factor erythroid 2-related factor 2; P53: Tumor suppressor protein p53; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS: Reactive oxygen species; Se: Selenium; SOD: Superoxide dismutase; T-Bil: Total bilirubin; tGSH: Total glutathione; TNFα: Tumor necrosis factor alpha; γ-GT: Gamma glutamyl transferase; Zn: Zinc.