Differential metabolites facilitate metabolic dysfunction-associated fatty liver disease malignancy via immune evasion and M2-polarized macrophages

doi:10.3748/wjg.117849

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World Journal of Gastroenterology

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1007-9327

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Jun 28, 2026; 32(24): 117849
Published online Jun 28, 2026. doi: 10.3748/wjg.117849

Table 1 Dynamic levels of lipids, enzymes and alpha-fetoprotein in the sera of the metabolic dysfunction-associated fatty liver disease rats

Group	n	Tch (mmol/L)	TG (mmol/L)	HDL (mmol/L)	LDL (mmol/L)	ALT (IU/L)	AST (IU/L)	AFP (ng/mL)
NC	6	1.32 ± 0.49	0.61 ± 0.19	2.20 ± 0.42	0.38 ± 0.09	14.75 ± 3.02	15.88 ± 3.29	0.88 ± 0.09
MAFLD	12	2.72 ± 0.46^a	0.99 ± 0.41^a	0.67 ± 0.20^a	1.19 ± 0.40^a	44.61 ± 14.34^a	44.86 ± 9.90^a	0.96 ± 0.30
MASH	11	3.76 ± 0.54^a	1.78 ± 0.25^a	1.36 ± 0.17^a	0.65 ± 0.09^a	62.19 ± 29.79^a	44.46 ± 9.25^a	1.46 ± 0.41
LC	13	3.29 ± 0.24^a	1.81 ± 0.27^a	1.17 ± 0.13^a	0.75 ± 0.09^a	55.75 ± 26.89^a	61.99 ± 18.21^a	1.60 ± 0.42
HCC	6	3.50 ± 0.60^a	1.22 ± 0.21^a	1.47 ± 0.11^a	0.63 ± 0.05^a	46.08 ± 13.39^a	47.91 ± 21.22^a	1.83 ± 0.54^a
F value		21.341	13.014	52.861	32.857	8.128	11.600	8.015
P value		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

^aP < 0.001 vs normal control group.

NC: Normal control; MAFLD: Metabolic dysfunction-associated fatty liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; LC: Liver cirrhosis; HCC: Hepatocellular carcinoma; Tch: Total cholesterol; TG: Triglyceride; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; ALT: Alanine aminotransferase; AST: Aspartate transaminase; AFP: Alpha-fetoprotein.

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Table 2 Dynamic transcription of metabolic dysfunction-associated fatty liver disease-related genes (mRNAs), mean ± SD

Gene	n	NC	MAFLD	MASH	LC	HCC
BAX (× 10⁴)	6	0.64 ± 0.91	0.66 ± 0.09	1.86 ± 0.39^b	1.93 ± 0.73^b	1.56 ± 0.16^b
CCND1 (× 10⁴)	6	1.64 ± 0.88	2.54 ± 1.35	6.44 ± 2.04^c	4.61 ± 1.04^b	4.88 ± 1.90^b
CDK1 (× 10³)	6	1.22 ± 0.59	1.46 ± 0.92	7.75 ± 2.48^c	7.32 ± 1.38^c	8.01 ± 2.48^c
CPT-II (× 10⁴)	6	5.41 ± 0.88	4.48 ± 0.31	4.02 ± 0.29^a	3.85 ± 0.43^a	3.66 ± 0.30^a
CYP1A1 (× 10⁴)	6	0.11 ± 0.05	0.08 ± 0.08	4.95 ± 3.79^b	3.84 ± 2.18^b	1.54 ± 0.32^a
CYP51 (× 10⁴)	6	4.90 ± 0.69	0.44 ± 0.13c	0.72 ± 0.30^c	1.14 ± 0.38^c	0.72 ± 0.18^c
EGR1 (× 10⁴)	6	1.64 ± 0.46	1.98 ± 0.40	1.74 ± 0.48	1.02 ± 0.10	0.94 ± 0.25
GAL3ST1 (× 10³)	6	0.73 ± 0.23	0.86 ± 0.22	1.10 ± 0.20	0.89 ± 0.19	1.57 ± 0.50^a
HEXB-β (× 10⁴)	6	1.90 ± 0.54	2.61 ± 0.68	2.32 ± 0.40	2.88 ± 0.88^a	3.27 ± 0.33^b
HOXD3 (× 10²)	6	8.21 ± 1.33	9.20 ± 2.17	8.16 ± 1.99	4.91 ± 0.62^a	4.75 ± 1.22^a
HSD17B7 (× 10³)	6	5.18 ± 1.38	1.14 ± 0.18^c	2.33 ± 0.47^c	2.35 ± 0.46^c	1.98 ± 0.77^c
LDHB (× 10³)	6	2.12 ± 1.16	2.01 ± 0.48	3.46 ± 1.54^a	3.57 ± 1.27^a	5.67 ± 3.31^c
MTHFR (× 10³)	6	2.20 ± 0.43	1.87 ± 0.50	1.45 ± 0.33	1.18 ± 0.34^a	1.43 ± 0.32^a
PPARγ (× 10³)	6	0.19 ± 0.69	3.34 ± 0.67^c	2.68 ± 0.74^c	3.05 ± 0.72^c	2.67 ± 0.97^c
PTDSS1 (× 10⁴)	6	2.26 ± 0.20	2.00 ± 0.17	1.86 ± 0.14^a	1.88 ± 0.11^a	1.90 ± 0.24^a
SAT2 (× 10⁴)	6	1.23 ± 0.22	1.48 ± 0.26	0.97 ± 0.22	0.69 ± 0.14^a	0.48 ± 0.08^a
SCD1 (× 10⁴)	6	3.17 ± 1.98	1.33 ± 0.88^a	0.26 ± 0.10^c	0.47 ± 0.22^c	0.87 ± 0.83^c
ST3GAL5 (× 10⁴)	6	0.65 ± 0.08	0.56 ± 0.06	0.73 ± 0.18	0.90 ± 0.22	1.31 ± 0.73^a
TYMP (× 10⁴)	6	3.59 ± 1.45	4.54 ± 1.18^a	3.19 ± 0.64	1.90 ± 0.33^c	1.63 ± 0.65^c

^aP < 0.05 vs normal control group.

^bP < 0.01 vs normal control group.

^cP < 0.001 vs normal control group.

NC: Normal control; MAFLD: Metabolic dysfunction-associated fatty liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; LC: Liver cirrhosis; HCC: Hepatocellular carcinoma.

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Table 3 Enrichment analysis of the top 10 genes associated with metabolic dysfunction-associated fatty liver disease malignancy

Group	Code	Biological function	P value¹	Gene symbol
MAFLD	rno00100	Steroid biosynthesis	< 0.001	Sc5d, Ebp, Msmo1, Cyp51, Sqle, Tm7sf2
	rno00900	Terpenoid backbone biosynthesis	< 0.001	Hmgcr, Hmgcs1, Pmvk, Mvd, Mvk
	rno05310	Asthma	0.002	RT1-Da, RT1-Db1, RT1-Bb, RT1-B1
	rno04672	IgA intestinal immune network	0.012	RT1-Da, RT1-Db1, RT1-Bb, RT1-B1
	rno04612	Antigen processing and presentation	0.014	Cd74, RT1-Da, RT1-Db1, RT1-Ba, RT1-Bb
	rno05332	Graft-vs-host disease	0.016	RT1-Da, RT1-Db1, RT1-Ba, RT1-Bb
	rno05330	Allograft rejection	0.018	RT1-Da, RT1-Db1, RT1-Ba, RT1-Bb
	rno04940	Type I diabetes mellitus	0.026	RT1-Da, RT1-Db1, RT1-Ba, RT1-Bb
	rno01040	Biosynthesis of unsaturated FA	0.026	Acaa1b, Fads2, Fads1
	rno05320	Autoimmune thyroid disease	0.026	RT1-Da, RT1-Db1, RT1-Ba, RT1-Bb
MASH	rno00100	Steroid biosynthesis	< 0.001	Ebp, Msmo1, Cyp51, Sqle, Tm7sf2
	rno00480	Glutathione metabolism	0.002	Ggt1, Gsr, Gclc, Gpx6, Gclm, Gsta3
	rno00260	Gly, Ser and Thr metabolism	0.003	Dao, Cbs, Agxt, Sds, Alas2, Psat1, Phgdh
	rno04115	p53 signaling pathway	0.003	Cdkn1a, Ccnb1, Ccng1, Gadd45b, Gtse1
	rno04540	Gap junction	0.004	Drd2, Egfr, Gja1, Gucy1b2, Pdgfa, Gnai1
	rno01040	Biosynthesis of unsaturated FA	0.005	Acot2, Acaa1b, Acot1, Acot4, Fads2, Fads1
	rno03320	PPAR signaling pathway	0.006	Acsl3, Lpl, Cyp7a1, Fabp2, Cyp4a8, Aqp7
	rno00830	Retinol metabolism	0.006	Aldh1a2, Cyp3a9, Aldh1a1, Cyp1a1
	rno04110	Cell cycle	0.006	Cdkn1a, Bub1b, Myc, Cdkn1c, Ccnb1
	rno00980	Xenobiotics by cytochrome P450	0.006	Cyp3a9, Cyp1a1, Cyp2c12, Aldh3a1
HCC	rno00100	Steroid biosynthesis	< 0.001	Sc5d, Ebp, Msmo1, Cyp51, Sqle
	rno04510	Focal adhesion	< 0.001	Ppp1r12a, Lama5, Lamc2, Egfr, Hgf
	rno04512	ECM-receptor interaction	< 0.001	Lama5, Lamc2, Ibsp, Itga1, Spp1, Hmmr
	rno04110	Cell cycle	< 0.001	Cdkn1a, Bub1b, Myc, Cdkn1c, Cdkn2a
	rno03320	PPAR signaling pathway	< 0.001	Acsl3, Acsl6, Olr1, Lpl, Me1, Cyp7a1
	rno00480	Glutathione metabolism	< 0.001	Ggt1, Gsr, G6pd, Gclc, Gpx2, Gclm
	rno04115	p53 signaling pathway	< 0.001	Cdkn1a, Fas, Serpine1, Cdkn2a, Ccnb1
	rno00340	Histidine metabolism	0.002	Ddc, Aldh3a1, Aldh1a3, Hal, Amdhd1
	rno05410	Hypertrophic cardiomyopathy	0.002	Tnnt2, Itga1, Itgb4, Atp2a2, Sgcg
	rno00980	Xenobiotics by cytochrome P450	0.008	Cyp3a9, Cyp1a1, Cyp2c12, Aldh3a1

¹Compared with the control group.

MAFLD: Metabolic dysfunction-associated fatty liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; HCC: Hepatocellular carcinoma; FA: Fatty acids; PPAR: Peroxisome proliferator-activated receptors; Gly: Glycine; Ser: Serine; Thr: Threonine; ECM: Extracellular matrix; IgA: Immunoglobulin A.

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Table 4 Top five up/downregulated differential metabolites during metabolic dysfunction-associated fatty liver disease progression

Groups	Top 5 upregulated	Top 5 downregulated
MAFLD vs NC	PC (16:0/22:4)	PC (18:0/18:3)
	PAF (36:4)	PC (36:0/20:3)
	PC (18:0/20:4)	dMePE (18:0/18:2)
	LPE (20:4)	SM (d16:0/26:2)
	PAF (38:6)	PAF (34:3)
HCC vs NC	PC (16:0/22:4)	PC (16:0/18:1)
	PAF (36:4)	PC (10:0/24:1)
	PC (18:0/20:4)	PAE (32:1)
	LPE (20:4)	PAF (34:1)
	PAF (38:6)	PC (18:0/18:1)
HCC vs MASH	dMePE (16:2/18:2)	PC (16:0/20:4)
	SM (d14:1/28:1)	PC (10:0/24:1)
	SM (d22:0/19:1)	PC (17:0/17:1)
	SM (d24:0/18:1)	PC (16:0/18:2)
	PC (18:0/18:3)	PAF (34:4)

NC: Normal control; MAFLD: Metabolic dysfunction-associated fatty liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; HCC: Hepatocellular carcinoma; PC: Phosphatidylcholine; PAF: Platelet-activating factor; LPE: Lysophosphatidylethanolamine; dMePE: Dimethylphosphatidylethanolamine; SM: Sphingomyelin.

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Citation: Yang J, Sai WL, Xia XX, Tang H, Xu M, Xie Q, Yao DF, Yao M. Differential metabolites facilitate metabolic dysfunction-associated fatty liver disease malignancy via immune evasion and M2-polarized macrophages. World J Gastroenterol 2026; 32(24): 117849
URL: https://www.wjgnet.com/1007-9327/full/v32/i24/117849.htm
DOI: https://dx.doi.org/10.3748/wjg.117849

Yang J, Sai WL, Xia XX, Tang H, Xu M, Xie Q, Yao DF, Yao M. Differential metabolites facilitate metabolic dysfunction-associated fatty liver disease malignancy via immune evasion and M2-polarized macrophages. World J Gastroenterol 2026; 32(24): 117849 [DOI: 10.3748/wjg.117849]

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