Mechanism of stem cell exosome-mediated repair of hepatocyte injury via mitochondrial and fatty acid metabolism

doi:10.12092/j.issn.1009-2501.2026.09.002

Abstract

Abstract:

AIM: To investigate the metabolic mechanism by which umbilical cord mesenchymal stem cell exosomes repair CCl₄-induced acute liver injury and to analyze the role of key metabolites in regulating the repair process. METHODS: The experiment was divided into three groups: the CCl₄ group, the CCl₄+low-dose exosome group, and the CCl₄+high-dose exosome group. Cell viability of HL-7702 cells, as well as levels of AST, ALT, and MDA, were measured. Targeted metabolomics analysis was performed to identify differential metabolites between the CCl₄ group and the CCl₄+exosome group. The co-localization relationship between exosomes and the nucleus or mitochondria in HL-7702 cells was observed using confocal laser scanning microscopy. Mitochondrial structural changes in each group were examined by transmission electron microscopy. RESULTS: Exosomes significantly reversed the decline in cell viability induced by 25 mmol/L CCl₄. Additionally, exosomes markedly reduced AST, ALT, and MDA levels. A total of 73 significantly differential metabolites were identified between the CCl₄ group and the CCl₄+exosome group, including glycodeoxycholic acid and tetradecanedioic acid. Fluorescence staining revealed co-localization of exosomes with both the nucleus and mitochondria. CONCLUSION: Exosomes significantly reversed the abnormal levels of AST, ALT, and MDA induced by CCl₄ in HL-7702 cells and protected mitochondrial structure against oxidative stress damage. Metabolomic findings suggest that exosomes may repair hepatocyte injury by mediating mitochondrial function and fatty acid metabolism.

Key words: liver injury, exosomes, mitochondria, fatty acid metabolism, metabonomics

CLC Number:

Xinxin YIN, Changpeng XIE, Xuejing LI, Liping ZHANG, Zhanhai SU, Haiyan WANG, Qiong WU, Yuanming PAN, Juan AN. Mechanism of stem cell exosome-mediated repair of hepatocyte injury via mitochondrial and fatty acid metabolism[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(9): 1162-1172.

Figures/Tables 7

References 22

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Compounds	Class	VIP	P value	FDR	Fold Change	Log2FC	Type
4-Guanidinobutanoic acid	Organic acids and their derivatives	1.124	0.122	0.284	3.364	1.750	Up
Oleoylethanolamide	Lipid amide	1.341	0.006	0.116	2.321	1.215	Up
Trigonelline	Coenzyme and vitamin	1.352	0.023	0.140	6.466	2.693	Up
Betaine	other	1.177	0.086	0.239	2.366	1.243	Up
Deoxycholic acid	Bile acid	1.416	0.001	0.038	2.540	1.345	Up
Betaine aldehyde chloride	Other	1.387	0.001	0.038	2.208	1.143	Up
Oleylcarnitine	Acylcarnitine	1.401	0.007	0.116	4.905	2.294	Up
DL-carnitine	Acylcarnitine	1.386	0.010	0.116	3.105	1.635	Up
Acetyl-carnitine	Acylcarnitine	1.121	0.124	0.285	2.802	1.486	Up
Myristoyl-L-carnitine	Acylcarnitine	1.321	0.038	0.166	2.837	1.504	Up
L-palmitoylcarnitine	Acylcarnitine	1.415	0.002	0.054	5.234	2.388	Up
Stearoyl-carnitine	Acylcarnitine	1.421	0.000	0.001	6.883	2.783	Up
Taurine	Sulfonic acid compounds	1.037	0.167	0.331	5.679	2.506	Up
N6-threonylcarbamoyladenosine	Nucleotides and their metabolites	1.295	0.041	0.166	2.150	1.104	Up
2'-O-methylcytidine	Nucleotides and their metabolites	1.411	0.000	0.012	2.490	1.316	Up
5'-Deoxy-5'-methylthioadensine	Nucleotides and their metabolites	1.041	0.161	0.325	2.377	1.249	Up
2'-O-methyluridine	Nucleotides and their metabolites	1.352	0.017	0.125	2.701	1.434	Up
5,2'-O-dimethyluridine	Nucleotides and their metabolites	1.320	0.037	0.166	5.325	2.413	Up
Pseudouridine	Nucleotides and their metabolites	1.319	0.041	0.166	2.305	1.205	Up
Uric acid	Purine and pyrimidine	1.004	0.187	0.336	6.589	2.720	Up
N,N-Dimethylguanosine	Nucleotides and their metabolites	1.255	0.066	0.204	2.725	1.446	Up
Thyroxine	Hormones and hormone-related substances	1.352	0.019	0.128	2.129	1.090	Up
Prostaglandin E2(PGE2)	Hormones and hormone-related substances	1.043	0.145	0.303	2.142	1.099	Up
Acetoacetic acid sodium salt	Organic acids and their derivatives	1.351	0.013	0.122	2.248	1.169	Up
Fumaric acid	Organic acids and their derivatives	1.242	0.069	0.206	2.694	1.430	Up
3-methylcytidine	Nucleotides and their metabolites	1.206	0.036	0.166	2.719	1.443	Up
Cyclic-AMP	Nucleotides and their metabolites	1.104	0.140	0.300	2.696	1.431	Up
Pyridoxine	Pyridine and its derivatives	1.088	0.140	0.300	19.293	4.270	Up
N-Palmitoylglycine	Amino acid derivatives	1.223	0.074	0.216	2.003	1.002	Up
N-A-Acetyl-L-Arginine	Amino acid derivatives	1.279	0.016	0.125	2.783	1.477	Up
4-Aminobutyric Acid	Amino acid derivatives	1.349	0.025	0.147	4.746	2.247	Up
Beta-Alanine	Amino acid derivatives	1.144	0.114	0.280	5.453	2.447	Up
L-Cystine	Amino acid	1.210	0.065	0.201	2.033	1.024	Up
Ribonic acid	Sugar acid	1.376	0.016	0.125	3.987	1.995	Up
Sphinganine	Amines	1.067	0.150	0.306	2.719	1.443	Up
gama-Glutamate-Cysteine	Small peptide	1.130	0.121	0.284	2.084	1.059	Up
Trans-4-Hydroxy-L-Proline	Amino acid derivatives	1.086	0.140	0.300	7.293	2.867	Up
Stachydrine hydrochloride	Organic acids and their derivatives	1.229	0.063	0.200	11.336	3.503	Up
Anserine	Small peptide	1.100	0.108	0.270	3.582	1.841	Up
Indolelactic acid	Indole and its derivatives	1.076	0.117	0.283	7.036	2.815	Up
1-Methyladenine	Nucleotides and their metabolites	1.385	0.016	0.125	Inf	Inf	Up
Myo-Inositol	Alcohol and polyol	1.023	0.172	0.336	Inf	Inf	Up
5-hydroxymethylcytidine	Nucleotides and their metabolites	1.277	0.052	0.186	Inf	Inf	Up
Glycodeoxycholic acid	Bile acid	1.422	0.001	0.038	Inf	Inf	Up
Allantoin	Imidazoles	1.258	0.064	0.201	Inf	Inf	Up
Arachidonylcarnitine	acylcarnitine	1.401	0.009	0.116	Inf	Inf	Up
Glycolithocholic acid	Bile acid	1.416	0.002	0.060	Inf	Inf	Up
Dodecanoylcarnitine	Acylcarnitine	1.161	0.106	0.270	Inf	Inf	Up
Deoxyuridine	Nucleotides and their metabolites	1.006	0.184	0.336	Inf	Inf	Up
Salicylic acid	Benzene and its derivatives	1.006	0.185	0.336	Inf	Inf	Up
3-hydroxymethylglutaric acid	Amino acid derivatives	1.002	0.188	0.336	Inf	Inf	Up
7a,27-Dihydroxycholesterol	Hormones and hormone-related substances	1.003	0.188	0.336	Inf	Inf	Up
Cholic acid	bile acid	1.005	0.184	0.336	Inf	Inf	Up
L-Cystathionine	Amino acid derivative	1.006	0.184	0.336	Inf	Inf	Up
3-Hydroxy-9-hexadecenoyl-L-carnitine	Acylcarnitine	1.006	0.184	0.336	Inf	Inf	Up
Vitamin B3	Coenzyme and vitamin	1.072	0.142	0.301	0.479	?1.061	Down
Tridecanedioic acid	Fatty acyl	1.286	0.050	0.182	0.413	?1.275	Down
Tetradecanedioic acid	Fatty acyl	1.331	0.030	0.159	0.394	?1.343	Down
Thiamine pyrophosphate	Coenzyme and vitamin	1.378	0.001	0.038	0.361	?1.471	Down
BPG	Phosphoric acid compounds	1.185	0.037	0.166	0.421	?1.248	Down
2-Picolinic Acid	Pyridine and its derivatives	1.166	0.096	0.250	0.426	?1.233	Down
Gly-Trp	Small peptide	1.255	0.055	0.188	0.392	?1.350	Down
Phe Leu	Small peptide	1.315	0.009	0.116	0.413	?1.275	Down
N,N-dimethylarginine	Amino acid derivatives	1.401	0.007	0.116	0.142	?2.819	Down
L-Alanyl-L-proline	Small peptide	1.288	0.032	0.159	0.474	?1.077	Down
Gly-Val	Small peptide	1.286	0.014	0.125	0.316	?1.661	Down
Mannitol	Sugar alcohol	1.208	0.060	0.196	0.424	?1.239	Down
Ser-Glu	Small peptide	1.342	0.019	0.128	0.311	?1.683	Down
Thr-Leu	Small peptide	1.294	0.012	0.121	0.452	?1.146	Down
Phe Val	Small peptide	1.319	0.014	0.125	0.351	?1.509	Down
Dodecanedioic Acid	Fatty acyl	1.226	0.027	0.152	0.304	?1.716	Down
Adenine	Nucleotides and their metabolites	1.139	0.087	0.239	0.120	?3.062	Down
Benzoic acid	Benzene and its derivatives	1.016	0.184	0.336	0.000	?Inf	Down

Compounds	Class	VIP	P value	FDR	Fold Change	Log2FC	Type
4-Guanidinobutanoic acid	Organic acids and their derivatives	1.124	0.122	0.284	3.364	1.750	Up
Oleoylethanolamide	Lipid amide	1.341	0.006	0.116	2.321	1.215	Up
Trigonelline	Coenzyme and vitamin	1.352	0.023	0.140	6.466	2.693	Up
Betaine	other	1.177	0.086	0.239	2.366	1.243	Up
Deoxycholic acid	Bile acid	1.416	0.001	0.038	2.540	1.345	Up
Betaine aldehyde chloride	Other	1.387	0.001	0.038	2.208	1.143	Up
Oleylcarnitine	Acylcarnitine	1.401	0.007	0.116	4.905	2.294	Up
DL-carnitine	Acylcarnitine	1.386	0.010	0.116	3.105	1.635	Up
Acetyl-carnitine	Acylcarnitine	1.121	0.124	0.285	2.802	1.486	Up
Myristoyl-L-carnitine	Acylcarnitine	1.321	0.038	0.166	2.837	1.504	Up
L-palmitoylcarnitine	Acylcarnitine	1.415	0.002	0.054	5.234	2.388	Up
Stearoyl-carnitine	Acylcarnitine	1.421	0.000	0.001	6.883	2.783	Up
Taurine	Sulfonic acid compounds	1.037	0.167	0.331	5.679	2.506	Up
N6-threonylcarbamoyladenosine	Nucleotides and their metabolites	1.295	0.041	0.166	2.150	1.104	Up
2'-O-methylcytidine	Nucleotides and their metabolites	1.411	0.000	0.012	2.490	1.316	Up
5'-Deoxy-5'-methylthioadensine	Nucleotides and their metabolites	1.041	0.161	0.325	2.377	1.249	Up
2'-O-methyluridine	Nucleotides and their metabolites	1.352	0.017	0.125	2.701	1.434	Up
5,2'-O-dimethyluridine	Nucleotides and their metabolites	1.320	0.037	0.166	5.325	2.413	Up
Pseudouridine	Nucleotides and their metabolites	1.319	0.041	0.166	2.305	1.205	Up
Uric acid	Purine and pyrimidine	1.004	0.187	0.336	6.589	2.720	Up
N,N-Dimethylguanosine	Nucleotides and their metabolites	1.255	0.066	0.204	2.725	1.446	Up
Thyroxine	Hormones and hormone-related substances	1.352	0.019	0.128	2.129	1.090	Up
Prostaglandin E2(PGE2)	Hormones and hormone-related substances	1.043	0.145	0.303	2.142	1.099	Up
Acetoacetic acid sodium salt	Organic acids and their derivatives	1.351	0.013	0.122	2.248	1.169	Up
Fumaric acid	Organic acids and their derivatives	1.242	0.069	0.206	2.694	1.430	Up
3-methylcytidine	Nucleotides and their metabolites	1.206	0.036	0.166	2.719	1.443	Up
Cyclic-AMP	Nucleotides and their metabolites	1.104	0.140	0.300	2.696	1.431	Up
Pyridoxine	Pyridine and its derivatives	1.088	0.140	0.300	19.293	4.270	Up
N-Palmitoylglycine	Amino acid derivatives	1.223	0.074	0.216	2.003	1.002	Up
N-A-Acetyl-L-Arginine	Amino acid derivatives	1.279	0.016	0.125	2.783	1.477	Up
4-Aminobutyric Acid	Amino acid derivatives	1.349	0.025	0.147	4.746	2.247	Up
Beta-Alanine	Amino acid derivatives	1.144	0.114	0.280	5.453	2.447	Up
L-Cystine	Amino acid	1.210	0.065	0.201	2.033	1.024	Up
Ribonic acid	Sugar acid	1.376	0.016	0.125	3.987	1.995	Up
Sphinganine	Amines	1.067	0.150	0.306	2.719	1.443	Up
gama-Glutamate-Cysteine	Small peptide	1.130	0.121	0.284	2.084	1.059	Up
Trans-4-Hydroxy-L-Proline	Amino acid derivatives	1.086	0.140	0.300	7.293	2.867	Up
Stachydrine hydrochloride	Organic acids and their derivatives	1.229	0.063	0.200	11.336	3.503	Up
Anserine	Small peptide	1.100	0.108	0.270	3.582	1.841	Up
Indolelactic acid	Indole and its derivatives	1.076	0.117	0.283	7.036	2.815	Up
1-Methyladenine	Nucleotides and their metabolites	1.385	0.016	0.125	Inf	Inf	Up
Myo-Inositol	Alcohol and polyol	1.023	0.172	0.336	Inf	Inf	Up
5-hydroxymethylcytidine	Nucleotides and their metabolites	1.277	0.052	0.186	Inf	Inf	Up
Glycodeoxycholic acid	Bile acid	1.422	0.001	0.038	Inf	Inf	Up
Allantoin	Imidazoles	1.258	0.064	0.201	Inf	Inf	Up
Arachidonylcarnitine	acylcarnitine	1.401	0.009	0.116	Inf	Inf	Up
Glycolithocholic acid	Bile acid	1.416	0.002	0.060	Inf	Inf	Up
Dodecanoylcarnitine	Acylcarnitine	1.161	0.106	0.270	Inf	Inf	Up
Deoxyuridine	Nucleotides and their metabolites	1.006	0.184	0.336	Inf	Inf	Up
Salicylic acid	Benzene and its derivatives	1.006	0.185	0.336	Inf	Inf	Up
3-hydroxymethylglutaric acid	Amino acid derivatives	1.002	0.188	0.336	Inf	Inf	Up
7a,27-Dihydroxycholesterol	Hormones and hormone-related substances	1.003	0.188	0.336	Inf	Inf	Up
Cholic acid	bile acid	1.005	0.184	0.336	Inf	Inf	Up
L-Cystathionine	Amino acid derivative	1.006	0.184	0.336	Inf	Inf	Up
3-Hydroxy-9-hexadecenoyl-L-carnitine	Acylcarnitine	1.006	0.184	0.336	Inf	Inf	Up
Vitamin B3	Coenzyme and vitamin	1.072	0.142	0.301	0.479	?1.061	Down
Tridecanedioic acid	Fatty acyl	1.286	0.050	0.182	0.413	?1.275	Down
Tetradecanedioic acid	Fatty acyl	1.331	0.030	0.159	0.394	?1.343	Down
Thiamine pyrophosphate	Coenzyme and vitamin	1.378	0.001	0.038	0.361	?1.471	Down
BPG	Phosphoric acid compounds	1.185	0.037	0.166	0.421	?1.248	Down
2-Picolinic Acid	Pyridine and its derivatives	1.166	0.096	0.250	0.426	?1.233	Down
Gly-Trp	Small peptide	1.255	0.055	0.188	0.392	?1.350	Down
Phe Leu	Small peptide	1.315	0.009	0.116	0.413	?1.275	Down
N,N-dimethylarginine	Amino acid derivatives	1.401	0.007	0.116	0.142	?2.819	Down
L-Alanyl-L-proline	Small peptide	1.288	0.032	0.159	0.474	?1.077	Down
Gly-Val	Small peptide	1.286	0.014	0.125	0.316	?1.661	Down
Mannitol	Sugar alcohol	1.208	0.060	0.196	0.424	?1.239	Down
Ser-Glu	Small peptide	1.342	0.019	0.128	0.311	?1.683	Down
Thr-Leu	Small peptide	1.294	0.012	0.121	0.452	?1.146	Down
Phe Val	Small peptide	1.319	0.014	0.125	0.351	?1.509	Down
Dodecanedioic Acid	Fatty acyl	1.226	0.027	0.152	0.304	?1.716	Down
Adenine	Nucleotides and their metabolites	1.139	0.087	0.239	0.120	?3.062	Down
Benzoic acid	Benzene and its derivatives	1.016	0.184	0.336	0.000	?Inf	Down

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