Table 1.

Natural products that target macrophage for nonalcoholic steatohepatitis therapy

Section	Drugs	Model	Functions	Ref.
Macrophage activation	Sparstolonin B	HFD-fed mice	↓CD68, MCP-1	[23]
	Curcuminoids	LPS-treated BALB/C mice	↓Phagocytic activity of KCs	[24]
	S. miltiorrhiza extract	CCl4-induced liver injury rats	↓p38, NF-κB signaling	[25]
	Extract of Graptopetalum paraguayense	Liver fibrosis rats, primary HSCs and KCs	↓KC activation, nitric oxide, TNF-α, IL-6	[26]
	Alisma orientale extract	PA-stimulated HepG2 cells, NAFLD mice	↓ER stress, lipogenic gene expression	[30,31]
	Myriocin	Co-culture SPT with myriocin	↓SPT activation	[32]
	Gallic acid	HFD-induced NAFLD mice	↓TMA, DMA	[37]
	Berberine	NAFLD mice	↓Clostridium cluster XIVa and IV;	[38]
	Dendrobium extract	db/db mice	↑The bacteroidetes to firmicutes ratio, Prevotella, Akkermansia; ↓S24-7, Rikenella, Escherichia coli.	[39]
	Dihydromyricetin	Adult NAFLD patients	↓Resistin, IR	[40]
	Korean Red Ginseng	NAFLD patients	↑Adiponectin, ↓TNF-α	[41]
	Total alkaloids of Rubus alceaefolius Poir	HFD-fed NAFLD rats	↑Adiponectin; ↓Leptin, resistin	[42]
	Opuntia ficus indica	Obese Zucker (fa/fa) rats	↑Adiponectin; ↓leptin, IR	[43]
	Umbelliferone	HFD- and STZ-induced type 2 diabetic rats	↑Adiponectin; ↓leptin, IR	[44]
	Piperine	HFD-induced obese rats	↑Adiponectin; ↓leptin, IR	[45]
Macrophage recruitment	Flavonoids	Mice	↓CCR2, CXCL10, CCR10	[48]
	Broccoli	DSS-induced colitis mice	↓CCR2	[49]
	Berberine	HFD-fed rats	↓CCL2	[50]
	Rudgea viburnoides (Cham.) Benth. (Rubiaceae) leaves	HC-diet fed BALB/c mice	↓CCL2	[51]
	Total aralosides of Aralia elata (Miq) seem	HFD-induced NASH mice, ApoE-/- mice	↓CCL2, JNK signaling pathway	[52]
Macrophage polarization	Celastrol	RAW264.7 cells and diet-induced obese mice	↓TNF-α, IL-6, IL-1β, iNOS, MAPK activation, NF-κB nuclear translocation; ↑Nrf2 and HO-1	[64]
	Smiglaside A	LPS-stimulated RAW264.7 cells, mouse peritoneal macrophages	↑AMPK-PPARγ, M2-type macrophages; ↓M1-type macrophages	[65]
	Asperlin	LPS-stimulated RAW264.7 cells	↓TNF-α, IL-1β, iNOS; ↑IL-4, IL-10	[66]
	The pentacyclic triterpene lupeol	DSS-induced colitis mice	↓TNF-α, IL-6, IL-1β, IL-12, p38, MAPK, CD86, IRF5; ↑IL-10, CD206	[67]
	Baicalin	BMDMs, PMs, colitis mice	↓TNF-α, IL-6, IL-23, IRF5; ↑IL-10, Arg-1, IRF4	[68,69]
	Tanshinone IIA	HFD fed ApoE-/- mice	↑M2-type macrophage, ↓miR-375	[70]
	Tabebuia avellanedae Lorentz ex Griseb extract	Mesenteric lymph nodes of DSS-induced colitis mice	↑M2-type macrophage	[71]
	Emodin	Primary mouse macrophages	↓NF-κB/IRF5/STAT1 and IRF4/STAT6 signaling, H3K27 acetylation; ↑H3K27 trimethylation	[10]
	Trichosanthes kirilowii lectin	STZ-induced diabetic DN rats	↓Notch signaling	[73]
	Oridonin	LPS-stimulated RAW264.7 cells	↓Notch signaling	[74]
Macrophage metabolism	Ampelopsis brevipedunculata (Vitaceae) berries	Ferrous iron-stimulated rat hepatocyte	↓Pyruvate, superoxide dismutase, dimethyl sulfoxide	[94]
	Aim Scutellariae Radix and Coptidis Rhizoma	HFD-induced diabetic rats	↑Pyruvate kinase activities	[95]
	Hyacinth bean	HFD-fed mice	↓Pyruvate-derived amino acids metabolism	[96]
	Mycetia cauliflora Reinw.	LPS-activated RAW264.7 cells	↓PDK1, NF-κB signaling pathway	[98]
	Dipterocarpus tuberculatus Roxb.	LPS-activated RAW264.7 cells	↓PDK1, NF-κB signaling pathway	[99]

HFD: High fat diet; LPS: lipopolysaccharide; KCs: Kupffer cells; CCl4: Carbon tetrachloride; HSCs: Hepatic stellate cells; NAFLD: Non-alcoholic fatty liver disease; SPT: Serine palmitoyltransferase; DMA: Dimethylamine; TMA: Trimethylamine; CCR2: C-C motif receptor; CXCL10: Chemokine ligand 10; DSS: Dextran sulfate sodium; HC: High refined carbohydrate; JNK: c-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; iNOS: Inducible nitric oxide synthase; IRF: Interferon regulatory factor; PDK: Pyruvate dehydrogenase kinase; IL: Interleukin; TNF: Tumor necrosis factor; CCR2: C-C motif receptor 2; MCP: Monocyte chemotactic protein; NF-κB: Nuclear factor-kappa B.