药学学报

No.	Identification	Formula	Ion adduction	Error/ppm	t_R/min	Measured mass	Normalized data	Fragment ion	Source
1	Ginsenoside Rb1	C₅₄H₉₂O₂₃	[M+COOH]^-	-0.5	17.80	1 153.600 0	0.019 6 ± 0.011 5	1 107.594 3, 945.568 5, 783.493 7, 621.445 4	G
2	Malonyl ginsenoside Rb1	C₅₇H₉₄O₂₆	[M-H]^-	0.0	18.12	1 193.596 1	0.014 2 ± 0.010 2	1 149.610 3, 1 089.584 8, 927.520 8, 179.057 1	G
3	Ginsenoside Rg1^*	C₄₂H₇₂O₁₄	[M+COOH]^-	-0.4	13.38	845.489 3	0.003 0 ± 0.001 5	475.372 1, 637.428 3, 799.495 1	G
4	Ginsenoside Rd	C₄₈H₈₂O₁₈	[M+COOH]^-	0.0	20.03	991.547 2	0.011 5 ± 0.006 0	945.536 2, 621.442 8, 783.489 0, 161.046 6	G
5	Ginsenoside Re^*	C₄₈H₈₂O₁₈	[M+COOH]^-	-0.3	13.36	991.547 2	0.001 8 ± 0.002 0	945.543 1, 799.485 5, 637.434 8, 619.420 9	G
6	Ginsenoside Rc	C₅₃H₉₀O₂₂	[M+COOH]^-	-0.2	18.70	1 123.589 5	0.008 6 ± 0.005 1	1 077.659 1, 945.534 9, 783.491 7, 149.048 5	G
7	Malonyl ginsenoside Rc	C₅₆H₉₂O₂₅	[M-H]^-	0.2	17.60	1 163.585 5	0.011 2 ± 0.002 8	1 077.591 8, 1 059.580 0	G
8	Schisanhenol	C₂₃H₃₀O₆	[M+H]⁺	-0.1	40.01	403.211 5	0.026 9 ± 0.007 9	371.184 7, 340.166 6, 271.257 2, 301.089 8	S
9	Schisandrin A^*	C₂₄H₃₂O₆	[M+H]⁺	-0.3	44.06	417.227 2	0.265 1 ± 0.136 7	402.204 1, 386.204 4, 316.130 7, 301.105 5	S
10	Schisandrol A^*	C₂₄H₃₂O₇	[M+H]⁺	-0.5	25.67	433.222 1	0.488 4 ± 0.297 2	415.208 4, 400.187 1, 384.193 4, 369.169 5	S
11	Gomisin D^*	C₂₈H₃₄O₁₀	[M+H]⁺	-0.8	27.76	531.222 5	0.347 8 ± 0.149 8	401.157 5, 353.136 6, 326.114 7	S
12	Benzoylgomisin Q	C₃₁H₃₆O₉	[M+H]⁺	0.1	35.99	553.243 2	0.065 0 ± 0.070 7	453.187 6, 387.177 1, 356.162 0, 343.118 4	S
13	Rubrisandrin B	C₂₂H₂₈O₆	[M+H]⁺	0.1	22.71	389.195 9	0.024 2 ± 0.006 6	389.218 9, 357.168 8, 325.135 2, 288.099 9	S
14	Gomisin N	C₂₃H₂₈O₆	[M+H]⁺	0.2	45.82	401.195 9	0.039 2 ± 0.029 8	386.171 2, 300.100 6, 285.074 8, 242.094 5	S
15	Schisandrin B^*	C₂₃H₂₈O₆	[M+H]⁺	-0.4	46.25	401.195 9	0.515 3 ± 0.164 1	386.170 4, 370.167 7, 300.097 2, 285.074 0	S
16	Schisandrol B^*	C₂₃H₂₈O₇	[M+Na]⁺	0.5	29.37	417.190 8	0.013 6 ± 0.007 1	399.158 4, 369.167 0, 368.160 2, 353.139 1	S
17	Gomisin S	C₂₃H₃₀O₇	[M+Na]⁺	0.2	20.15	441.188 4	0.097 4 ± 0.086 1	369.171 1, 337.142 3, 323.129 5, 301.105 3	S
18	Schisantherin C	C₂₈H₃₄O₉	[M+H]⁺	-0.2	39.20	515.227 6	0.025 7 ± 0.010 2	437.147 9, 415.175 4, 385.161 3, 371.147 9	S
19	Angeloygomisin H^*	C₂₈H₃₆O₈	[M+Na]⁺	0.1	34.22	501.248 3	0.015 9 ± 0.009 4	483.231 6, 401.196 6, 370.177 6, 337.146 6	S
20	Schisphenlignan A	C₂₉H₃₀O₉	[M+H]⁺	-4.2	29.87	523.196 3	0.041 6 ± 0.019 7	423.139 3, 383.143 7, 352.129 7, 341.102 6	S
21	Angeloylgomisin Q	C₂₉H₃₈O₉	[M+Na]⁺	0.0	35.99	553.240 8	0.066 3 ± 0.071 7	453.192 4, 431.192 4, 387.184 2, 358.140 9	S
22	Benzoylgomisin P	C₃₀H₃₂O₉	[M+H]⁺	-1.8	38.11	537.211 9	0.041 4 ± 0.021 2	437.163 2, 415.169 5, 371.149 0, 340.129 8	S

No.

Identification

Formula

Ion adduction

Error/ppm

t_R/min

Measured mass

Normalized data

Fragment ion

Source

Ginsenoside Rb1

C₅₄H₉₂O₂₃

[M+COOH]^-

-0.5

17.80

1 153.600 0

0.019 6 ± 0.011 5

1 107.594 3, 945.568 5, 783.493 7, 621.445 4

Malonyl ginsenoside Rb1

C₅₇H₉₄O₂₆

[M-H]^-

0.0

18.12

1 193.596 1

0.014 2 ± 0.010 2

1 149.610 3, 1 089.584 8, 927.520 8, 179.057 1

Ginsenoside Rg1^*

C₄₂H₇₂O₁₄

[M+COOH]^-

-0.4

13.38

845.489 3

0.003 0 ± 0.001 5

475.372 1, 637.428 3, 799.495 1

Ginsenoside Rd

C₄₈H₈₂O₁₈

[M+COOH]^-

0.0

20.03

991.547 2

0.011 5 ± 0.006 0

945.536 2, 621.442 8, 783.489 0, 161.046 6

Ginsenoside Re^*

C₄₈H₈₂O₁₈

[M+COOH]^-

-0.3

13.36

991.547 2

0.001 8 ± 0.002 0

945.543 1, 799.485 5, 637.434 8, 619.420 9

Ginsenoside Rc

C₅₃H₉₀O₂₂

[M+COOH]^-

-0.2

18.70

1 123.589 5

0.008 6 ± 0.005 1

1 077.659 1, 945.534 9, 783.491 7, 149.048 5

Malonyl ginsenoside Rc

C₅₆H₉₂O₂₅

[M-H]^-

0.2

17.60

1 163.585 5

0.011 2 ± 0.002 8

1 077.591 8, 1 059.580 0

Schisanhenol

C₂₃H₃₀O₆

[M+H]⁺

-0.1

40.01

403.211 5

0.026 9 ± 0.007 9

371.184 7, 340.166 6, 271.257 2, 301.089 8

Schisandrin A^*

C₂₄H₃₂O₆

[M+H]⁺

-0.3

44.06

417.227 2

0.265 1 ± 0.136 7

402.204 1, 386.204 4, 316.130 7, 301.105 5

Schisandrol A^*

C₂₄H₃₂O₇

[M+H]⁺

-0.5

25.67

433.222 1

0.488 4 ± 0.297 2

415.208 4, 400.187 1, 384.193 4, 369.169 5

Gomisin D^*

C₂₈H₃₄O₁₀

[M+H]⁺

-0.8

27.76

531.222 5

0.347 8 ± 0.149 8

401.157 5, 353.136 6, 326.114 7

Benzoylgomisin Q

C₃₁H₃₆O₉

[M+H]⁺

0.1

35.99

553.243 2

0.065 0 ± 0.070 7

453.187 6, 387.177 1, 356.162 0, 343.118 4

Rubrisandrin B

C₂₂H₂₈O₆

[M+H]⁺

0.1

22.71

389.195 9

0.024 2 ± 0.006 6

389.218 9, 357.168 8, 325.135 2, 288.099 9

Gomisin N

C₂₃H₂₈O₆

[M+H]⁺

0.2

45.82

401.195 9

0.039 2 ± 0.029 8

386.171 2, 300.100 6, 285.074 8, 242.094 5

Schisandrin B^*

C₂₃H₂₈O₆

[M+H]⁺

-0.4

46.25

401.195 9

0.515 3 ± 0.164 1

386.170 4, 370.167 7, 300.097 2, 285.074 0

Schisandrol B^*

C₂₃H₂₈O₇

[M+Na]⁺

0.5

29.37

417.190 8

0.013 6 ± 0.007 1

399.158 4, 369.167 0, 368.160 2, 353.139 1

Gomisin S

C₂₃H₃₀O₇

[M+Na]⁺

0.2

20.15

441.188 4

0.097 4 ± 0.086 1

369.171 1, 337.142 3, 323.129 5, 301.105 3

Schisantherin C

C₂₈H₃₄O₉

[M+H]⁺

-0.2

39.20

515.227 6

0.025 7 ± 0.010 2

437.147 9, 415.175 4, 385.161 3, 371.147 9

Angeloygomisin H^*

C₂₈H₃₆O₈

[M+Na]⁺

0.1

34.22

501.248 3

0.015 9 ± 0.009 4

483.231 6, 401.196 6, 370.177 6, 337.146 6

Schisphenlignan A

C₂₉H₃₀O₉

[M+H]⁺

-4.2

29.87

523.196 3

0.041 6 ± 0.019 7

423.139 3, 383.143 7, 352.129 7, 341.102 6

Angeloylgomisin Q

C₂₉H₃₈O₉

[M+Na]⁺

0.0

35.99

553.240 8

0.066 3 ± 0.071 7

453.192 4, 431.192 4, 387.184 2, 358.140 9

Benzoylgomisin P

C₃₀H₃₂O₉

[M+H]⁺

-1.8

38.11

537.211 9

0.041 4 ± 0.021 2

437.163 2, 415.169 5, 371.149 0, 340.129 8

No.	Identification	Formula	Ion adduction	Error/ppm	t_R/min	Measured mass	Normalized data	Fragment ion	Source
1	Ginsenoside Rb1	C₅₄H₉₂O₂₃	[M+COOH]^-	-0.5	17.80	1 153.600 0	0.019 6 ± 0.011 5	1 107.594 3, 945.568 5, 783.493 7, 621.445 4	G
2	Malonyl ginsenoside Rb1	C₅₇H₉₄O₂₆	[M-H]^-	0.0	18.12	1 193.596 1	0.014 2 ± 0.010 2	1 149.610 3, 1 089.584 8, 927.520 8, 179.057 1	G
3	Ginsenoside Rg1^*	C₄₂H₇₂O₁₄	[M+COOH]^-	-0.4	13.38	845.489 3	0.003 0 ± 0.001 5	475.372 1, 637.428 3, 799.495 1	G
4	Ginsenoside Rd	C₄₈H₈₂O₁₈	[M+COOH]^-	0.0	20.03	991.547 2	0.011 5 ± 0.006 0	945.536 2, 621.442 8, 783.489 0, 161.046 6	G
5	Ginsenoside Re^*	C₄₈H₈₂O₁₈	[M+COOH]^-	-0.3	13.36	991.547 2	0.001 8 ± 0.002 0	945.543 1, 799.485 5, 637.434 8, 619.420 9	G
6	Ginsenoside Rc	C₅₃H₉₀O₂₂	[M+COOH]^-	-0.2	18.70	1 123.589 5	0.008 6 ± 0.005 1	1 077.659 1, 945.534 9, 783.491 7, 149.048 5	G
7	Malonyl ginsenoside Rc	C₅₆H₉₂O₂₅	[M-H]^-	0.2	17.60	1 163.585 5	0.011 2 ± 0.002 8	1 077.591 8, 1 059.580 0	G
8	Schisanhenol	C₂₃H₃₀O₆	[M+H]⁺	-0.1	40.01	403.211 5	0.026 9 ± 0.007 9	371.184 7, 340.166 6, 271.257 2, 301.089 8	S
9	Schisandrin A^*	C₂₄H₃₂O₆	[M+H]⁺	-0.3	44.06	417.227 2	0.265 1 ± 0.136 7	402.204 1, 386.204 4, 316.130 7, 301.105 5	S
10	Schisandrol A^*	C₂₄H₃₂O₇	[M+H]⁺	-0.5	25.67	433.222 1	0.488 4 ± 0.297 2	415.208 4, 400.187 1, 384.193 4, 369.169 5	S
11	Gomisin D^*	C₂₈H₃₄O₁₀	[M+H]⁺	-0.8	27.76	531.222 5	0.347 8 ± 0.149 8	401.157 5, 353.136 6, 326.114 7	S
12	Benzoylgomisin Q	C₃₁H₃₆O₉	[M+H]⁺	0.1	35.99	553.243 2	0.065 0 ± 0.070 7	453.187 6, 387.177 1, 356.162 0, 343.118 4	S
13	Rubrisandrin B	C₂₂H₂₈O₆	[M+H]⁺	0.1	22.71	389.195 9	0.024 2 ± 0.006 6	389.218 9, 357.168 8, 325.135 2, 288.099 9	S
14	Gomisin N	C₂₃H₂₈O₆	[M+H]⁺	0.2	45.82	401.195 9	0.039 2 ± 0.029 8	386.171 2, 300.100 6, 285.074 8, 242.094 5	S
15	Schisandrin B^*	C₂₃H₂₈O₆	[M+H]⁺	-0.4	46.25	401.195 9	0.515 3 ± 0.164 1	386.170 4, 370.167 7, 300.097 2, 285.074 0	S
16	Schisandrol B^*	C₂₃H₂₈O₇	[M+Na]⁺	0.5	29.37	417.190 8	0.013 6 ± 0.007 1	399.158 4, 369.167 0, 368.160 2, 353.139 1	S
17	Gomisin S	C₂₃H₃₀O₇	[M+Na]⁺	0.2	20.15	441.188 4	0.097 4 ± 0.086 1	369.171 1, 337.142 3, 323.129 5, 301.105 3	S
18	Schisantherin C	C₂₈H₃₄O₉	[M+H]⁺	-0.2	39.20	515.227 6	0.025 7 ± 0.010 2	437.147 9, 415.175 4, 385.161 3, 371.147 9	S
19	Angeloygomisin H^*	C₂₈H₃₆O₈	[M+Na]⁺	0.1	34.22	501.248 3	0.015 9 ± 0.009 4	483.231 6, 401.196 6, 370.177 6, 337.146 6	S
20	Schisphenlignan A	C₂₉H₃₀O₉	[M+H]⁺	-4.2	29.87	523.196 3	0.041 6 ± 0.019 7	423.139 3, 383.143 7, 352.129 7, 341.102 6	S
21	Angeloylgomisin Q	C₂₉H₃₈O₉	[M+Na]⁺	0.0	35.99	553.240 8	0.066 3 ± 0.071 7	453.192 4, 431.192 4, 387.184 2, 358.140 9	S
22	Benzoylgomisin P	C₃₀H₃₂O₉	[M+H]⁺	-1.8	38.11	537.211 9	0.041 4 ± 0.021 2	437.163 2, 415.169 5, 371.149 0, 340.129 8	S

No.

Identification

Formula

Ion adduction

Error/ppm

t_R/min

Measured mass

Normalized data

Fragment ion

Source

Ginsenoside Rb1

C₅₄H₉₂O₂₃

[M+COOH]^-

-0.5

17.80

1 153.600 0

0.019 6 ± 0.011 5

1 107.594 3, 945.568 5, 783.493 7, 621.445 4

Malonyl ginsenoside Rb1

C₅₇H₉₄O₂₆

[M-H]^-

0.0

18.12

1 193.596 1

0.014 2 ± 0.010 2

1 149.610 3, 1 089.584 8, 927.520 8, 179.057 1

Ginsenoside Rg1^*

C₄₂H₇₂O₁₄

[M+COOH]^-

-0.4

13.38

845.489 3

0.003 0 ± 0.001 5

475.372 1, 637.428 3, 799.495 1

Ginsenoside Rd

C₄₈H₈₂O₁₈

[M+COOH]^-

0.0

20.03

991.547 2

0.011 5 ± 0.006 0

945.536 2, 621.442 8, 783.489 0, 161.046 6

Ginsenoside Re^*

C₄₈H₈₂O₁₈

[M+COOH]^-

-0.3

13.36

991.547 2

0.001 8 ± 0.002 0

945.543 1, 799.485 5, 637.434 8, 619.420 9

Ginsenoside Rc

C₅₃H₉₀O₂₂

[M+COOH]^-

-0.2

18.70

1 123.589 5

0.008 6 ± 0.005 1

1 077.659 1, 945.534 9, 783.491 7, 149.048 5

Malonyl ginsenoside Rc

C₅₆H₉₂O₂₅

[M-H]^-

0.2

17.60

1 163.585 5

0.011 2 ± 0.002 8

1 077.591 8, 1 059.580 0

Schisanhenol

C₂₃H₃₀O₆

[M+H]⁺

-0.1

40.01

403.211 5

0.026 9 ± 0.007 9

371.184 7, 340.166 6, 271.257 2, 301.089 8

Schisandrin A^*

C₂₄H₃₂O₆

[M+H]⁺

-0.3

44.06

417.227 2

0.265 1 ± 0.136 7

402.204 1, 386.204 4, 316.130 7, 301.105 5

Schisandrol A^*

C₂₄H₃₂O₇

[M+H]⁺

-0.5

25.67

433.222 1

0.488 4 ± 0.297 2

415.208 4, 400.187 1, 384.193 4, 369.169 5

Gomisin D^*

C₂₈H₃₄O₁₀

[M+H]⁺

-0.8

27.76

531.222 5

0.347 8 ± 0.149 8

401.157 5, 353.136 6, 326.114 7

Benzoylgomisin Q

C₃₁H₃₆O₉

[M+H]⁺

0.1

35.99

553.243 2

0.065 0 ± 0.070 7

453.187 6, 387.177 1, 356.162 0, 343.118 4

Rubrisandrin B

C₂₂H₂₈O₆

[M+H]⁺

0.1

22.71

389.195 9

0.024 2 ± 0.006 6

389.218 9, 357.168 8, 325.135 2, 288.099 9

Gomisin N

C₂₃H₂₈O₆

[M+H]⁺

0.2

45.82

401.195 9

0.039 2 ± 0.029 8

386.171 2, 300.100 6, 285.074 8, 242.094 5

Schisandrin B^*

C₂₃H₂₈O₆

[M+H]⁺

-0.4

46.25

401.195 9

0.515 3 ± 0.164 1

386.170 4, 370.167 7, 300.097 2, 285.074 0

Schisandrol B^*

C₂₃H₂₈O₇

[M+Na]⁺

0.5

29.37

417.190 8

0.013 6 ± 0.007 1

399.158 4, 369.167 0, 368.160 2, 353.139 1

Gomisin S

C₂₃H₃₀O₇

[M+Na]⁺

0.2

20.15

441.188 4

0.097 4 ± 0.086 1

369.171 1, 337.142 3, 323.129 5, 301.105 3

Schisantherin C

C₂₈H₃₄O₉

[M+H]⁺

-0.2

39.20

515.227 6

0.025 7 ± 0.010 2

437.147 9, 415.175 4, 385.161 3, 371.147 9

Angeloygomisin H^*

C₂₈H₃₆O₈

[M+Na]⁺

0.1

34.22

501.248 3

0.015 9 ± 0.009 4

483.231 6, 401.196 6, 370.177 6, 337.146 6

Schisphenlignan A

C₂₉H₃₀O₉

[M+H]⁺

-4.2

29.87

523.196 3

0.041 6 ± 0.019 7

423.139 3, 383.143 7, 352.129 7, 341.102 6

Angeloylgomisin Q

C₂₉H₃₈O₉

[M+Na]⁺

0.0

35.99

553.240 8

0.066 3 ± 0.071 7

453.192 4, 431.192 4, 387.184 2, 358.140 9

Benzoylgomisin P

C₃₀H₃₂O₉

[M+H]⁺

-1.8

38.11

537.211 9

0.041 4 ± 0.021 2

437.163 2, 415.169 5, 371.149 0, 340.129 8

Target	Binding energy / kcal·mol^-1
FXR	-6.2	-6.0	-7.5
CYP7A1	-7.2	-6.5	-8.4
BSEP	-6.5	-8.1	-6.1
OATP1B1	-6.3	-7.4	-9.4

Target

Binding energy / kcal·mol^-1

Ginsenoside Rb1

Schisandrin A

Target inhibitor

FXR

-6.2

-6.0

-7.5

CYP7A1

-7.2

-6.5

-8.4

BSEP

-6.5

-8.1

-6.1

OATP1B1

-6.3

-7.4

-9.4

Target	Binding energy / kcal·mol^-1
FXR	-6.2	-6.0	-7.5
CYP7A1	-7.2	-6.5	-8.4
BSEP	-6.5	-8.1	-6.1
OATP1B1	-6.3	-7.4	-9.4

Target

Binding energy / kcal·mol^-1

Ginsenoside Rb1

Schisandrin A

Target inhibitor

FXR

-6.2

-6.0

-7.5

CYP7A1

-7.2

-6.5

-8.4

BSEP

-6.5

-8.1

-6.1

OATP1B1

-6.3

-7.4

-9.4

基于靶向胆汁酸代谢组学与分子对接技术的“人参-五味子”药对治疗肝细胞癌的药效物质与作用机制研究

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官丽芳 , 李赛玉 , 董怡静 , 张明哲 , 张倩 , 许华容 , 李清 , 张译文 ^*

药学学报 | 研究论文 2026,61(5): 1793-1803

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药学学报 |研究论文 2026 , 61 (5) : 1793 -1803

基于靶向胆汁酸代谢组学与分子对接技术的“人参-五味子”药对治疗肝细胞癌的药效物质与作用机制研究

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官丽芳, 李赛玉, 董怡静, 张明哲, 张倩, 许华容, 李清, 张译文^*

作者信息

沈阳药科大学药学院, 辽宁沈阳 110016

通讯作者:

张译文，Tel: 86-24-43520086, E-mail: zzzyyywen@outlook.com

作者简介:

作者贡献:

官丽芳负责本文的选题与研究设计、实验方法建立、实验实施、数据处理分析及文章撰写。李赛玉为实验思路及文章撰写提供了针对性指导。董怡静参与前期实验方法摸索与验证, 协助数据处理。张明哲在样品制备、预处理及相关实验操作提供了帮助。张倩、许华容、李清对选题设计、实验方法及文章修改提出建设性意见。张译文指导实验思路与文章撰写, 对本文实验方法建立及文章修改提供了宝贵意见, 并提供基金支持。

Study on the pharmacodynamic substances and mechanism of "Ginseng-Schisandra" herb pair in the treatment of hepatocellular carcinoma based on targeted bile acid metabolomics and molecular docking technology

Li-fang GUAN, Sai-yu LI, Yi-jing DONG, Ming-zhe ZHANG, Qian ZHANG, Hua-rong XU, Qing LI, Yi-wen ZHANG^*

Affiliations

School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China

出版时间: 2026-05-12 doi: 10.16438/j.0513-4870.2025-1409

文章导航

摘要

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本研究旨在探讨“人参-五味子”药对治疗肝细胞癌(hepatocellular carcinoma, HCC) 的药效物质与作用机制。研究采用高效液相色谱-四级杆飞行时间质谱(HPLC-QTOF/MS) 技术分析“人参-五味子”药对入血成分。基于LC-MS技术全面分析“人参-五味子”药对干预后HCC大鼠血浆、肝脏和粪便中胆汁酸(bile acid, BA) 水平变化, 结合正交偏最小二乘判别分析(orthogonal partial least squares-discriminant analysis, OPLS-DA) 和t检验筛选HCC相关生物标志物。最后, 基于相关性分析确定“人参-五味子”药对治疗HCC的关键药效物质, 并通过分子对接技术进行验证。本实验经过沈阳药科大学伦理委员会批准(伦理审批号: No. CSE202106002)。研究结果鉴定了22种“人参-五味子”药对入血原型成分, 证实了“人参-五味子”药对能够显著回调HCC大鼠血浆、肝脏和粪便中BA代谢失调, 并成功筛选了9种BA为HCC相关生物标志物。相关性分析和分子对接结果表明, 人参皂苷Rb1和五味子甲素与BA代谢调控关键蛋白法尼醇X受体(farnesoid X receptor, FXR)、胆固醇7α-羟化酶(cytochrome P450 family 7 subfamily A member 1, CYP7A1)、胆汁酸盐输出泵(bile salt export pump, BSEP) 和有机阴离子转运多肽1B1 (organic anion transporting polypeptide 1B1, OATP1B1) 均具有较强的结合活性, 是“人参-五味子”药对治疗HCC的关键药效物质。研究结果为“人参-五味子”药对治疗HCC的临床应用提供了科学依据。

关键词

"人参-五味子"药对 / 肝细胞癌 / 胆汁酸 / 药效物质 / 作用机制

Abstract

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This study aims to investigate the potential active components and mechanism of action of "Ginseng-Schisandra" herb pair in the treatment of hepatocellular carcinoma (HCC). The blood-entering components of the "Ginseng-Schisandra" herb pair were identified using high pressure liquid chromatography-quadrupole-time of flight mass spectrometry (HPLC-QTOF/MS). The alterations of bile acid (BA) levels in the plasma, liver, and feces of HCC rats following intervention with the "Ginseng-Schisandra" herb pair were comprehensively analyzed by LC-MS. The biomarkers of HCC were screened by integrating orthogonal partial least squares-discriminant analysis (OPLS-DA) and Student's t-test. Finally, the key pharmacodynamic substances of "Ginseng-Schisandra" herb pair in the treatment of HCC were identified based on correlation analysis and further verified through molecular docking. The animal experiments were approved by the Ethics Committee of Shenyang Pharmaceutical University (approval No.: CSE202106002). As a result, 22 blood-entering prototype components of the "Ginseng-Schisandra" herb pair were identified. This study demonstrated that the "Ginseng-Schisandra" herb pair markedly restored dysregulated BA metabolism in the plasma, liver, and feces of HCC rats, and 9 bile acids were successfully characterized as HCC biomarkers. Correlation analysis and molecular docking demonstrated that ginsenoside Rb1 and schisandrin A, which exhibited strong binding affinities to key BA regulatory proteins [farnesoid X receptor (FXR), cytochrome P450 family 7 subfamily A member 1 (CYP7A1), bile salt export pump (BSEP), and organic anion transporting polypeptide 1B1 (OATP1B1)], were crucial pharmacodynamic constituents of the "Ginseng-Schisandra" herb pair in the treatment of HCC. Collectively, this study established a scientific foundation for the clinical application of the "Ginseng-Schisandra" herb pair in the treatment of HCC.

Key words

"Ginseng-Schisandra" herb pair / hepatocellular carcinoma / bile acid / pharmacodynamic substance / mechanism of action

引用本文

官丽芳, 李赛玉, 董怡静, 张明哲, 张倩, 许华容, 李清, 张译文. 基于靶向胆汁酸代谢组学与分子对接技术的“人参-五味子”药对治疗肝细胞癌的药效物质与作用机制研究. 药学学报, 2026 , 61 (5) : 1793 -1803 . DOI: 10.16438/j.0513-4870.2025-1409

Li-fang GUAN, Sai-yu LI, Yi-jing DONG, Ming-zhe ZHANG, Qian ZHANG, Hua-rong XU, Qing LI, Yi-wen ZHANG. Study on the pharmacodynamic substances and mechanism of "Ginseng-Schisandra" herb pair in the treatment of hepatocellular carcinoma based on targeted bile acid metabolomics and molecular docking technology[J]. Acta Pharmaceutica Sinica, 2026 , 61 (5) : 1793 -1803 . DOI: 10.16438/j.0513-4870.2025-1409

正文

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肝细胞癌(hepatocellular carcinoma, HCC) 是常见的原发性肝癌, 具有发病隐匿、恶性程度高且转移速度快等特点, 五年生存率仅为22%^[1], 严重威胁人类健康。目前HCC的临床治疗手段以手术切除和化学药物治疗为主, 尽管取得了一定的进展, 但仍面临术后复发与化疗耐药等诸多挑战, 患者总体预后仍然较差^{[2, 3]}。因此, 亟需寻找疗效显著且安全性高的HCC治疗药物。近年来, 中药因其“多成分、多靶点”的作用特点, 以及来源广泛和不良反应小等优势, 在治疗HCC方面展现出独特的优势。

越来越多的研究表明, 胆汁酸(bile acid, BA) 代谢紊乱是驱动HCC发生的关键风险因素^{[4, 5]}。BA作为胆固醇代谢的终产物和重要的信号分子, 不仅参与脂质的消化吸收, 还通过激活法尼醇X受体(farnesoid X receptor, FXR)、G蛋白偶联胆汁酸受体1 (Takeda G protein-coupled receptor 5, TGR5) 等调控肝细胞的增殖、凋亡和氧化应激反应^{[6, 7]}。肝脏中BA异常蓄积会诱发氧化应激与炎症反应, 并激活多种增殖信号通路, 从而促进HCC的发生和发展^[8-10]。因此, 靶向调节BA稳态可能是治疗HCC的关键策略。然而, 目前通过中药调控BA代谢治疗HCC的研究仍然有限。

人参(Panax ginseng C. A. Mey.) 和五味子[Schisandra chinensis (Turcz.) Baill.] 为临床常用药对。其中人参大扶元气、补脾养血; 五味子收敛固涩, 益气生津。二者相使为用, 人参主补气虚, 五味子辅助收敛气散, 健脾理气, 亦有养肝、护肝之功效^[11]。现代药理学研究表明人参和五味子中多种活性成分具有肝保护活性^[12-15]。且已有研究表明人参和五味子配伍后, 五味子木脂素类成分能够通过抑制P-糖蛋白(P-glycoprotein, P-gp) 和细胞色素P450 3A4 (cytochrome P450 family 3 subfamily A polypeptide 4, CYP3A4) 促进人参中主要活性成分人参皂苷类成分的吸收, 为联合用药以增强疗效提供了理论依据^[16]。此外, “人参-五味子”药对在预防酒精性肝损伤、调节BA稳态方面表现出显著潜力^{[17, 18]}。然而“人参-五味子”药对能否可以通过调控BA代谢紊乱治疗HCC尚不清晰。因此, 本研究以“人参-五味子”药对为研究对象, 拟采用靶向胆汁酸代谢组学与分子对接技术相结合的分析策略, 系统分析“人参-五味子”药对治疗HCC的关键药效物质和作用机制, 为HCC的临床治疗提供新的理论依据和潜在治疗策略。

材料与方法

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仪器 1260 Infinity Ⅱ型HPLC (美国安捷伦公司); TripleTOF^TM 5600⁺串联质谱仪(AB SCIEX公司); 4000 QTRAP^TM串联质谱仪(美国Sciex公司); BP210S电子分析天平(德国Sartorius公司); SCIENTZ-IID超声波细胞粉碎机(宁波新芝生物科技有限公司); KQ5200B超声波清洗器(昆山市超声仪器有限公司); TGL-16高速台式低温离心机(湖南湘仪实验室仪器开发有限公司); MTN-2800D氮吹浓缩仪(天津奥特赛恩斯仪器有限公司)。

药品与试剂 人参(17112314)、五味子(1610315) 均购自沈阳市天益堂药店, 经沈阳药科大学中药学院王东教授鉴定, 分别为五加科植物人参Panax ginseng C. A. Mey.的干燥根和根茎及木兰科植物五味子Schisandra chinensis (Turcz.) Baill.的干燥成熟果实。甲酸(色谱纯, C14547533, 上海麦克林生化科技股份有限公司); 无水乙醇(色谱纯, 20231008011, 山东禹王和天下新材料有限公司); 乙腈(F24OB4202)、甲醇(F24OBB214) 均为色谱纯, 购自美国Fisher有限公司; 纯净水(杭州娃哈哈有限公司); 戈米辛O (DG0053)、当归酰基戈米辛H (DD0061) 均购自成都德思特生物技术有限公司; 地高辛(CHB-D-139)、五味子乙素(CHB-W-090)、戈米辛D (CHB-G-086)、人参皂苷Ro (CHB-R-034) 均来自成都克洛玛生物科技有限公司; 联苯双酯(B27150)、人参皂苷Rg1 (B21057)、人参皂苷Re (B21055)、人参皂苷Rb1 (B21050)、人参皂苷Rc (B21053)、人参皂苷Rg3 (B21759)、五味子甲素(B21326)、五味子醇甲(B21322)、五味子醇乙(B21323) 均从上海源叶生物科技有限公司购买。

实验动物 30只雄性Wistar大鼠(100 ± 20 g) 购自长生生物制药有限公司, 许可证号为CXK (辽) 2020-0001。所有动物饲养于SPF级屏障环境中, 温度为23 ± 2 ℃, 湿度为65% ± 15%。动物实验经沈阳药科大学伦理委员会批准(伦理审批号: CSE202106002)。

“人参-五味子”药对溶液的制备 按4∶6的质量比称取人参、五味子粉末适量, 加入10倍量体积分数70%无水乙醇, 加热回流提取1 h, 趁热过滤并回收滤液。残渣加10倍量体积分数70%无水乙醇, 重复上述操作, 合并两次滤液, 真空浓缩至膏状, 用质量分数0.5%羧甲基纤维素钠复溶至1.25 g·mL^-1。

HCC大鼠模型的建立及给药方案 30只大鼠随机分为空白组、模型组和“人参-五味子”药对给药组, 每组10只。模型组和给药组大鼠每周腹腔注射一次体积分数10%亚硝基二乙胺(70 mg·kg^-1) 溶液, 空白组注射等量生理盐水, 持续10周。给药组于第8周开始灌胃“人参-五味子”药对溶液(2.5 g·kg^-1, 生药材量/体质量), 空白组和模型组灌胃纯净水, 每日一次, 持续至20周。实验结束后, 采集各组大鼠血浆、肝脏组织和粪便样品, -80 ℃储存, 以备后续的入血成分分析及靶向胆汁酸代谢组学分析。

“人参-五味子”药对入血成分分析

色谱条件 Phenomenex Kinetex XB-C₁₈色谱柱(100 mm × 4.6 mm, 2.6 μm)。流动相: 0.1%甲酸水(A)-0.1%甲酸乙腈(B)。梯度洗脱程序为: 0~15 min, 90%~60% A; 15~30 min, 60%~50% A; 30~40 min, 50%~30% A; 40~50 min, 30%~10% A; 50~52 min, 10%~90% A; 52~60 min, 90% A。流速: 0.5 mL·min^-1, 柱温: 30 ℃, 进样量: 5 μL。

质谱条件离子源: 电喷雾离子源; 检测模式: 正、负离子采集; 离子源温度: 550 ℃; 离子喷雾电压: 5 500 V和-4 500 V; 喷雾气(N₂)、辅助加热气(N₂) 及气帘气(N₂) 压力分别为50、50、30 psi; 雾化气及其余辅助气体均为N₂。TOF MS模式下扫描范围为m/z 100~2 000 Da, 碰撞能: 10 V (正离子) /-10 V (负离子); 去簇电压: 80 V (正离子) /-80 V (负离子)。TOF MS/MS模式下扫描范围为m/z 50~2 000 Da, 碰撞能: 50 ± 15 V (正离子) /-60 ± 5 V (负离子); 去簇电压: 80 V (正离子) /-80 V (负离子)。

对照品及内标溶液的制备分别称取人参皂苷Ro、人参皂苷Rb1、人参皂苷Rg1、人参皂苷Rg3、人参皂苷Re、人参皂苷Rc、五味子甲素、五味子乙素、五味子醇甲、五味子醇乙、戈米辛D、戈米辛O、当归酰基戈米辛H对照品适量, 精密称定, 用70%无水乙醇配制成浓度为200 μg·mL^-1的混合对照品储备液。分别取对照品联苯双酯、地高辛适量, 精密称定, 分别用甲醇-水(90∶10)、甲醇溶解配制成5 μg·mL^-1的联苯双酯内标溶液和10 μg·mL^-1的地高辛内标溶液。

血浆样品的预处理取给药组大鼠血浆200 μL, 加入10 μL地高辛内标溶液, 添加3倍量甲醇沉淀蛋白, 涡旋3 min, 离心5 min (12 000 r·min^-1, 4 ℃), 取上清液于氮气流下吹干, 残留物加100 μL联苯双酯内标溶液复溶, 涡旋3 min, 超声5 min, 离心5 min (12 000 r·min^-1, 4 ℃), 取上清液进样分析。

靶向胆汁酸谱分析

本研究采用团队先前报道的BA定量方法对血浆、肝脏和粪便样品中的BA进行定量分析^[19]。分析采用高效液相色谱-串联质谱(HPLC-MS/MS) 系统, 其中色谱条件、质谱条件、系列标准溶液的制备、内标溶液的制备和衍生化试剂溶液的制备方法均参照先前方法。

血浆样品预处理取血浆样品100 μL, 加入甲醇及混合内标各10 μL, 涡旋30 s, 加入冷甲醇500 μL, 涡旋3 min, 离心10 min (12 000 r·min^-1, 4 ℃), 取上清液于氮气流下吹干。依次向其中加入1-羟基苯并三唑、2-(7-偶氮苯并三氮唑)-N, N, N', N'-四甲基脲六氟磷酸酯、N1, N1-二乙基丁烷-1, 4-二胺和三乙胺溶液各30 μL, 涡旋30 s, 室温下反应1 min, 离心5 min (12 000 r·min^-1, 4 ℃), 取上清液进样分析。

肝脏组织预处理称取肝脏组织样品(50.00 ± 0.50 mg), 加入生理盐水100 μL后将组织剪碎, 于冰浴条件下超声破碎3 min (150 W, 工作3 s, 间隙3 s), 得肝脏匀浆液。向匀浆液中加入甲醇及混合内标各10 μL, 涡旋30 s, 加入乙腈-异丙醇(1∶2) 混合溶液500 μL, 涡旋5 min, 超声5 min, 离心10 min (12 000 r·min^-1, 4 ℃), 取上清液于氮气流下吹干。其余步骤同“血浆样品预处理”。

粪便预处理粪便样品冷冻干燥48 h后研磨成粉末。称取冻干粉末(50.00 ± 0.50 mg), 加入生理盐水500 μL, 涡旋10 min, 超声10 min, 得粪便匀浆液。向匀浆液中加入甲醇及混合内标各10 μL, 涡旋30 s, 加入甲醇-乙腈-丙酮(1∶1∶1) 500 μL, 涡旋10 min, 超声10 min, 离心10 min (12 000 r·min^-1, 4 ℃), 取上清液并过滤(0.22 μm), 滤液于氮气流下吹干。其余步骤同“血浆样品预处理”。

相关性分析 采用SPSS 23.0软件对入血原型成分的相对含量与血浆、肝脏和粪便样本中HCC生物标志物水平进行皮尔逊相关性分析, 以评估入血成分与BA之间的相关性。

分子对接 从PDB数据库中获取受体蛋白FXR (PDB ID: 1osh)、胆固醇7α-羟化酶(cytochrome P450 family 7 subfamily A member 1, CYP7A1, PDB ID: 3v8d)、胆汁盐输出泵(bile salt export pump, BSEP, PDB ID: 8pmj) 及有机阴离子转运多肽1B1 (organic anion transporting polypeptide 1B1, OATP1B1, PDB ID: 8k6l) 的晶体结构, 并通过PubChem数据库得到配体成分的结构。使用Autodock Tools软件对蛋白和配体结构进行预处理, 包括去除水分子、添加氢原子, 并将其转化为pdbqt格式。随后, 在Autodock Vina软件中设置对接盒子参数, 进行半柔性对接, 并记录结合能。最后采用PyMol软件对分子对接结果进行可视化分析。

统计学分析 采用SPSS 23.0软件进行数据分析, 实验数据以均值±标准差(mean ± SD) 表示。多组间比较采用单因素方差分析(analysis of variance, ANOVA) 检验, 两组间比较采用独立样本t检验。P < 0.05认为差异具有统计学意义。

结果

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1　“人参-五味子”药对入血成分分析

运用建立的HPLC-QTOF/MS分析方法对“人参-五味子”药对入血成分进行分析。利用PeakView^® V2.2软件, 通过与对照品或文献报道过的人参、五味子中成分的色谱保留行为、精确分子量、裂解规律及碎片离子信息进行比对, 初步鉴定到22种入血成分, 其中7种成分来源于人参(均为人参皂苷类成分), 15种成分来源于五味子(均为木脂素类成分), 所有化合物质量误差均小于5 ppm。将化合物峰面积与内标峰面积比值作为归一化数据, 即为入血成分的半定量结果。入血成分鉴定结果及半定量结果见表1。

2　靶向胆汁酸代谢组学分析

2.1　“人参-五味子”药对对HCC大鼠血浆中胆汁酸代谢物水平的影响

据报道, 血浆中BA代谢异常可能增加HCC发生的风险^[20]。因此, 本研究分析了空白组、模型组及“人参-五味子”药对给药组大鼠血浆中6种游离型胆汁酸[胆酸(cholic acid, CA)、鹅去氧胆酸(chenodeoxycholic acid, CDCA)、熊去氧胆酸(ursodeoxycholic acid, UDCA)、石胆酸(lithocholic acid, LCA)、脱氧胆酸(deoxycholic acid, DCA)、猪去氧胆酸(hyodeoxycholic acid, HDCA)] 和11种结合型胆汁酸[牛磺胆酸(taurocholic acid, TCA)、牛磺鹅去氧胆酸(taurochenodeoxycholic acid, TCDCA)、牛磺熊去氧胆酸(tauroursodeoxycholic acid, TUDCA)、牛磺石胆酸(taurolithocholic acid, TLCA)、牛磺脱氧胆酸(taurodeoxycholic acid, TDCA)、甘氨胆酸(glycocholic acid, GCA)、甘氨鹅去氧胆酸(glycochenodeoxycholic acid, GCDCA)、甘氨熊去氧胆酸(glycoursodeoxycholic acid, GUDCA)、甘氨石胆酸(glycolithocholic acid, GLCA)、甘氨脱氧胆酸(glycodeoxycholic acid, GDCA)、甘氨猪去氧胆酸(glycohyodeoxycholic acid, GHDCA)] 的水平变化。如图1A~C所示, HCC大鼠血浆中总胆汁酸、总初级胆汁酸和总次级胆汁酸水平均显著高于空白组, 给予“人参-五味子”药对后显著逆转了这一现象。游离型胆汁酸分析结果表明(图1D), 与空白组相比, HCC大鼠血浆中CA、CDCA、UDCA、DCA和HDCA水平显著升高, LCA水平显著下降, 给予“人参-五味子”药对治疗后, 显著降低了CA、CDCA、UDCA、DCA和HDCA的异常升高。此外, 如图1E所示, 除了TLCA、GDCA、GLCA外, 其余8种结合型胆汁酸水平均发生了明显升高, 其中4种结合型胆汁酸(TCDCA、TUDCA、GUDCA、GHDCA) 水平经“人参-五味子”药对治疗后显著降低。这些结果提示“人参-五味子”药对可以有效改善HCC大鼠血浆中BA代谢紊乱。

2.2　“人参-五味子”药对对HCC大鼠肝脏中胆汁酸代谢物水平的影响

肝脏是BA合成的主要场所, 其功能异常可能导致BA稳态失衡, 而长期BA代谢紊乱可通过诱发慢性炎症和DNA损伤, 从而促进HCC的发生^{[21, 22]}。如图2A~C所示, 模型组大鼠肝脏总胆汁酸、总初级胆汁酸、总次级胆汁酸水平均显著高于空白组, 经“人参-五味子”药对治疗后得到了显著回调。其中, 游离型胆汁酸CA和DCA水平显著上升, LCA和HDCA水平发生了显著下调, “人参-五味子”药对干预后显著逆转了这些变化(图2D)。此外, 如图2E所示, “人参-五味子”药对能够显著回调HCC中结合型胆汁酸TCA、TDCA、TCDCA、TUDCA、GCDCA、GDCA、GUDCA和GCA水平的异常升高, 同时显著逆转GLCA水平的异常降低。这些结果表明, “人参-五味子”药对能够有效改善HCC引起的肝脏中BA紊乱, 显示出良好的肝保护作用。

2.3　“人参-五味子”药对对HCC大鼠粪便中胆汁酸代谢物水平的影响

肠道为次级胆汁酸合成的主要场所, 肠道内容物中的BA水平可反映肝胆功能及代谢稳态。本研究进一步监测了HCC大鼠粪便中BA代谢物水平。如图3A~C所示, 模型组大鼠粪便中总胆汁酸和总初级胆汁酸出现下降趋势, 这与血浆和肝脏样品中的结果相反。模型组大鼠粪便中总次级胆汁酸出现上升趋势。研究表明, 次级胆汁酸具有更高的疏水特性, 与肝脏毒性密切相关^[23]。如图3D、E所示, 与空白组相比, 模型组大鼠粪便中游离型胆汁酸UDCA、LCA和结合型胆汁酸TCA、TDCA、TCDCA、TUDCA、TLCA、GUDCA水平显著降低, 其中5种BA (TCA、TDCA、TCDCA、TUDCA、GUDCA) 水平与血浆及肝脏中BA的变化趋势相反。这一现象提示HCC中BA肝肠循环可能受损, 导致肝脏中BA外排受阻和肠道内BA重吸收减少, 这种循环障碍可能与BSEP、OATP1B1等转运蛋白功能异常密切相关。此外, HCC大鼠粪便中5种BA (CA、HDCA、GCDCA、GDCA、GCA) 水平较空白组显著升高。“人参-五味子”药对干预后, 大鼠粪便中9种BA (CA、UDCA、LCA、HDCA、TDCA、TCDCA、GCDCA、GDCA、GCA) 水平得到明显改善, 表明其可能通过修复BA转运体功能来改善代谢紊乱。

3　差异代谢物分析

为了筛选与HCC相关的生物标志物, 分别对空白组和模型组中血浆、肝脏及粪便样品进行了正交偏最小二乘判别分析(orthogonal partial least squares-discriminant analysis, OPLS-DA)。结果如图4A~C所示, 血浆、肝脏、粪便样品的OPLS-DA得分图表明, 空白组与模型组分离良好, 经过200次的置换检验, 验证了模型具有可靠性, 无过拟合风险, 这提示HCC中BA代谢发生了明显紊乱。以VIP ≥ 1且P < 0.05为筛选原则, 分别在血浆、肝脏和粪便中识别到5个(CA、TCA、GCA、TUDCA、HDCA)、3个(TCA、GCA、TDCA) 和5个(CA、HDCA、CDCA、UDCA、LCA) 差异代谢物。通过对上述差异代谢物取并集, 确定了9种BA (CA、TCA、GCA、TUDCA、HDCA、TDCA、CDCA、UDCA、LCA) 为HCC的生物标志物。

4　相关性分析

为了识别“人参-五味子”药对治疗HCC的潜在活性成分, 本研究将22种入血原型成分的半定量结果与筛选的9种HCC相关生物标志物的水平进行Pearson相关性分析。结果如图5所示, “人参-五味子”药对中多种活性成分与HCC大鼠血浆、肝脏和粪便中的多种BA呈强相关性(|γ| ≥ 0.8, P < 0.05)。说明“人参-五味子”药对干预后极大程度地回调了HCC中BA代谢物的水平。值得注意的是, 人参皂苷Rb1与粪便中CA及五味子甲素与血浆中CA水平之间的相关性系数超过了0.95, 推测这两种成分在“人参-五味子”药对治疗HCC过程中发挥关键作用。

5　分子对接验证

为了进一步验证“人参-五味子”药对治疗HCC的潜在药效物质, 本研究将筛选的人参皂苷Rb1和五味子甲素两个关键药效物质与BA代谢调控相关的关键蛋白靶点FXR、CYP7A1、BSEP和OATP1B1进行分子对接验证。结果显示, 所有配体与关键靶点的结合能均小于-5 kcal·mol^-1, 展现出良好的结合活性, 证实了它们之间存在较强的亲和力(表2)。如图6A~D [以人参皂苷Rb1及靶点抑制剂(奥贝胆酸(obeticholic acid, OCA)、CDCA、环孢霉素A、利福平为例] 所示, 人参皂苷Rb1与FXR、CYP7A1的对接结合能均接近于FXR、CYP7A1与靶点抑制剂OCA和CDCA的对接结合能, BSEP与人参皂苷Rb1的对接结合能高于其与环孢霉素A的对接结合能。值得注意的是, OATP1B1与人参皂苷Rb1对接及OATP1B1与利福平对接的结合位点(HIS-555、ARG-580) 完全相同。结合上述结果, 人参皂苷Rb1、五味子甲素与关键靶点具有较好的结合活性, 提示其可能通过作用于关键靶点产生治疗HCC的作用。

讨论

收起

HCC作为一种发病率高、死亡率高的恶性肿瘤, 是全球范围内一个严峻的公共卫生问题。“人参-五味子”药对展现出良好的治疗HCC的潜力。然而, 其治疗HCC的关键药效成分和作用机制尚不清晰。本研究首先采用HPLC-QTOF/MS技术, 鉴定了22种“人参-五味子”药对入血原型成分。随后基于靶向胆汁酸代谢组学探讨了“人参-五味子”药对对HCC胆汁酸代谢的调节作用, 并利用多变量统计分析方法识别了HCC相关生物标志物。最后通过相关性分析和分子对接技术阐明了“人参-五味子”药对治疗HCC的关键药效物质与作用机制。

总胆汁酸水平的变化能够体现机体的生理状态和损伤程度。研究证实, HCC患者的总胆汁酸谱具有独特的代谢特征^[24]。同时, 总胆汁酸的稳态主要取决于肝脏的外排和肠道的重吸收^[25]。为了探究HCC中BA代谢的具体情况, 本研究全面分析了血浆、肝脏组织和粪便样本中总胆汁酸代谢水平的变化。研究结果表明, HCC大鼠血浆和肝脏样品中总胆汁酸水平显著高于空白组, 已知高水平BA环境会诱发肝细胞中活性氧(reactive oxygen species, ROS) 的产生, 同时促进细胞凋亡, 进一步导致肝功能受损^[26]。此外, HCC大鼠粪便样品中总胆汁酸水平呈现下降的趋势, 由此可以推测HCC的发生与BA肝肠循环之间存在密切关系。同时, 本研究证实了“人参-五味子”药对的干预有效改善了总胆汁酸代谢的稳态失衡, 阐明了其在治疗HCC方面的巨大潜力。

本研究进一步量化了HCC大鼠血浆、肝脏组织和粪便样本中6种游离型胆汁酸和11种结合型胆汁酸水平的变化, 并探讨了“人参-五味子”药对的干预作用。研究结果表明, 3种样本中游离型胆汁酸CA水平均显著升高, 这可能是BA合成限速酶CYP7A1和细胞色素P450 8B1 (cytochrome P450 family 8 subfamily B member 1, CYP8B1) 表达上调, 同时胆汁淤积和胆道排泄障碍促进其累积导致^[27]。另外, HCC大鼠血浆、肝脏组织和粪便中游离型胆汁酸LCA水平均下降, 这可能是由于肠道菌群7α-脱羟基化活性增强促使了CDCA向LCA转化^[28]。游离型胆汁酸HDCA水平在血浆、粪便中升高, 而在肝脏中下降, 这可能与其独特的6α-羟基化结构相关, 这种结构阻碍了肝脏的再摄取^[29]。结合型胆汁酸GCA在各样本中水平均显著升高, 提示HCC中BAAT酶介导的结合反应增强^[30]。研究表明, 较高的牛磺酸结合型胆汁酸与肝脏损伤存在显著关联^[31]。本研究发现牛磺酸结合型胆汁酸TCA、TDCA、TCDCA、TUDCA水平在血浆、肝脏样本中均升高, 而在粪便中呈现下降的趋势。经“人参-五味子”药对治疗后, 上述异常变化的BA水平发生了显著的回调。

近年来研究表明, FXR、CYP7A1、BSEP和OATP1B1等靶点构成的BA信号通路在HCC发生发展过程中发挥着核心调控作用。FXR是BA稳态的主要调节器, 当FXR被BA激活后, 一方面FXR通过诱导小异二聚体伴侣(small heterodimer partner, SHP) 的表达, 抑制CYP7A1的转录, 从而负反馈减少BA的从头合成; 另一方面, FXR直接正调控BSEP的转录, 促进BA向胆管的排泄, 并通过抑制OATP1B1的内化来减少肝细胞对BA的再摄取, 从而维持肝内BA池的稳定^[32-34]。然而, FXR的表达在HCC发生过程中出现下调或功能丧失^[35]。FXR功能受损导致其对CYP7A1的抑制解除, 引起BA过度合成与肝内蓄积; 同时, BSEP表达减少或功能障碍造成BA排泄受阻, 而OATP1B1等摄取转运体的异常表达可能进一步加剧肝细胞内BA的毒性负荷^[36]。这种累积的毒性BA不仅直接诱发内质网应激、线粒体功能障碍和ROS大量产生, 导致DNA损伤和肝细胞凋亡或坏死, 进而引发代偿性增殖和炎症微环境, 从而加剧肝毒性^[37], 而且可通过持续激活EGFR/MAPK、JAK/STAT3等促癌通路, 驱动肝细胞的恶性转化与HCC的发生发展^[38]。基于BA及其相关调控蛋白在HCC发生过程中的关键作用, 本研究通过结合相关性分析和分子对接技术, 探讨了“人参-五味子”药对治疗HCC的关键药效物质和作用机制。研究结果表明, 人参皂苷Rb1和五味子甲素与多种BA呈强相关性, 且与FXR、CYP7A1、BSEP和OATP1B1靶点蛋白具有较强的结合活性。其中, 人参皂苷Rb1与粪便中CA水平呈现极显著相关性, 且与FXR、CYP7A1靶点具有更低的结合能, 推测其可能通过作用于FXR/CYP7A1信号通路显著改善BA肝肠循环^[39]。而五味子甲素与血浆CA水平具有显著相关性, 且与BSEP、OATP1B1胆汁酸转运蛋白具有更强的结合活性, 提示其可能通过作用于BSEP、OATP1B1等转运蛋白, 促进BA从肝细胞向胆道外排, 降低血浆中BA异常积聚。由此可见, 人参皂苷Rb1与五味子甲素分别从合成调控与转运排泄两个关键环节协同干预肝内BA稳态失衡, 可能是“人参-五味子”药对治疗HCC的潜在活性成分。同时, 这些结果进一步表明了“人参-五味子”药对通过多成分、多靶点协同发挥治疗HCC的作用特点。

综上所述, 本研究基于靶向胆汁酸代谢组学及分子对接技术, 初步表明了“人参-五味子”药对中的人参皂苷Rb1、五味子甲素等活性成分可能通过调控FXR、CYP7A1、BSEP、OATP1B1等关键靶点蛋白, 参与调节BA代谢紊乱, 从而发挥治疗HCC的作用。此外, 与前期研究相比^[11], 本研究进一步对“人参-五味子”药对入血成分进行了补充, 并通过半定量分析排除了含量极低的化合物, 为“人参-五味子”药对治疗HCC的药效物质筛选提供了更聚焦的化合物库, 同时提高了筛选的药效物质的可测性; 基于前期研究发现的BA代谢紊乱在HCC发生中的关键作用^[19], 本研究进一步从代谢调控角度切入, 系统阐明“人参-五味子”药对通过调节BA代谢网络治疗HCC的作用机制, 为该药对治疗HCC的临床应用提供了更多的理论依据; 通过将入血成分含量与BA代谢物水平进行相关性分析, 从而筛选出“人参-五味子”药对与HCC治疗效应密切相关的特异性药效物质群。研究结果不仅是对前期研究结果的补充, 而且进一步诠释了中药多成分、多靶点的整体调节的作用特点。未来研究可进一步结合体内外实验及多种生物学分析技术, 对筛选的“人参-五味子”药对的药效物质基础及直接作用的靶点进一步研究, 以推动“人参-五味子”药对的临床转化和应用。

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2026年第61卷第5期

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doi: 10.16438/j.0513-4870.2025-1409

接收时间：2025-11-26
首发时间：2026-09-21
出版时间：2026-05-12

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收稿日期：2025-11-26
修回日期：2026-02-11

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沈阳药科大学药学院, 辽宁沈阳 110016

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张译文，Tel: 86-24-43520086, E-mail: zzzyyywen@outlook.com

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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2025-1409

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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No.	Identification	Formula	Ion adduction	Error/ppm	t_R/min	Measured mass	Normalized data	Fragment ion	Source
1	Ginsenoside Rb1	C₅₄H₉₂O₂₃	[M+COOH]^-	-0.5	17.80	1 153.600 0	0.019 6 ± 0.011 5	1 107.594 3, 945.568 5, 783.493 7, 621.445 4	G
2	Malonyl ginsenoside Rb1	C₅₇H₉₄O₂₆	[M-H]^-	0.0	18.12	1 193.596 1	0.014 2 ± 0.010 2	1 149.610 3, 1 089.584 8, 927.520 8, 179.057 1	G
3	Ginsenoside Rg1^*	C₄₂H₇₂O₁₄	[M+COOH]^-	-0.4	13.38	845.489 3	0.003 0 ± 0.001 5	475.372 1, 637.428 3, 799.495 1	G
4	Ginsenoside Rd	C₄₈H₈₂O₁₈	[M+COOH]^-	0.0	20.03	991.547 2	0.011 5 ± 0.006 0	945.536 2, 621.442 8, 783.489 0, 161.046 6	G
5	Ginsenoside Re^*	C₄₈H₈₂O₁₈	[M+COOH]^-	-0.3	13.36	991.547 2	0.001 8 ± 0.002 0	945.543 1, 799.485 5, 637.434 8, 619.420 9	G
6	Ginsenoside Rc	C₅₃H₉₀O₂₂	[M+COOH]^-	-0.2	18.70	1 123.589 5	0.008 6 ± 0.005 1	1 077.659 1, 945.534 9, 783.491 7, 149.048 5	G
7	Malonyl ginsenoside Rc	C₅₆H₉₂O₂₅	[M-H]^-	0.2	17.60	1 163.585 5	0.011 2 ± 0.002 8	1 077.591 8, 1 059.580 0	G
8	Schisanhenol	C₂₃H₃₀O₆	[M+H]⁺	-0.1	40.01	403.211 5	0.026 9 ± 0.007 9	371.184 7, 340.166 6, 271.257 2, 301.089 8	S
9	Schisandrin A^*	C₂₄H₃₂O₆	[M+H]⁺	-0.3	44.06	417.227 2	0.265 1 ± 0.136 7	402.204 1, 386.204 4, 316.130 7, 301.105 5	S
10	Schisandrol A^*	C₂₄H₃₂O₇	[M+H]⁺	-0.5	25.67	433.222 1	0.488 4 ± 0.297 2	415.208 4, 400.187 1, 384.193 4, 369.169 5	S
11	Gomisin D^*	C₂₈H₃₄O₁₀	[M+H]⁺	-0.8	27.76	531.222 5	0.347 8 ± 0.149 8	401.157 5, 353.136 6, 326.114 7	S
12	Benzoylgomisin Q	C₃₁H₃₆O₉	[M+H]⁺	0.1	35.99	553.243 2	0.065 0 ± 0.070 7	453.187 6, 387.177 1, 356.162 0, 343.118 4	S
13	Rubrisandrin B	C₂₂H₂₈O₆	[M+H]⁺	0.1	22.71	389.195 9	0.024 2 ± 0.006 6	389.218 9, 357.168 8, 325.135 2, 288.099 9	S
14	Gomisin N	C₂₃H₂₈O₆	[M+H]⁺	0.2	45.82	401.195 9	0.039 2 ± 0.029 8	386.171 2, 300.100 6, 285.074 8, 242.094 5	S
15	Schisandrin B^*	C₂₃H₂₈O₆	[M+H]⁺	-0.4	46.25	401.195 9	0.515 3 ± 0.164 1	386.170 4, 370.167 7, 300.097 2, 285.074 0	S
16	Schisandrol B^*	C₂₃H₂₈O₇	[M+Na]⁺	0.5	29.37	417.190 8	0.013 6 ± 0.007 1	399.158 4, 369.167 0, 368.160 2, 353.139 1	S
17	Gomisin S	C₂₃H₃₀O₇	[M+Na]⁺	0.2	20.15	441.188 4	0.097 4 ± 0.086 1	369.171 1, 337.142 3, 323.129 5, 301.105 3	S
18	Schisantherin C	C₂₈H₃₄O₉	[M+H]⁺	-0.2	39.20	515.227 6	0.025 7 ± 0.010 2	437.147 9, 415.175 4, 385.161 3, 371.147 9	S
19	Angeloygomisin H^*	C₂₈H₃₆O₈	[M+Na]⁺	0.1	34.22	501.248 3	0.015 9 ± 0.009 4	483.231 6, 401.196 6, 370.177 6, 337.146 6	S
20	Schisphenlignan A	C₂₉H₃₀O₉	[M+H]⁺	-4.2	29.87	523.196 3	0.041 6 ± 0.019 7	423.139 3, 383.143 7, 352.129 7, 341.102 6	S
21	Angeloylgomisin Q	C₂₉H₃₈O₉	[M+Na]⁺	0.0	35.99	553.240 8	0.066 3 ± 0.071 7	453.192 4, 431.192 4, 387.184 2, 358.140 9	S
22	Benzoylgomisin P	C₃₀H₃₂O₉	[M+H]⁺	-1.8	38.11	537.211 9	0.041 4 ± 0.021 2	437.163 2, 415.169 5, 371.149 0, 340.129 8	S

No.

Identification

Formula

Ion adduction

Error/ppm

t_R/min

Measured mass

Normalized data

Fragment ion

Source

Ginsenoside Rb1

C₅₄H₉₂O₂₃

[M+COOH]^-

-0.5

17.80

1 153.600 0

0.019 6 ± 0.011 5

1 107.594 3, 945.568 5, 783.493 7, 621.445 4

Malonyl ginsenoside Rb1

C₅₇H₉₄O₂₆

[M-H]^-

0.0

18.12

1 193.596 1

0.014 2 ± 0.010 2

1 149.610 3, 1 089.584 8, 927.520 8, 179.057 1

Ginsenoside Rg1^*

C₄₂H₇₂O₁₄

[M+COOH]^-

-0.4

13.38

845.489 3

0.003 0 ± 0.001 5

475.372 1, 637.428 3, 799.495 1

Ginsenoside Rd

C₄₈H₈₂O₁₈

[M+COOH]^-

0.0

20.03

991.547 2

0.011 5 ± 0.006 0

945.536 2, 621.442 8, 783.489 0, 161.046 6

Ginsenoside Re^*

C₄₈H₈₂O₁₈

[M+COOH]^-

-0.3

13.36

991.547 2

0.001 8 ± 0.002 0

945.543 1, 799.485 5, 637.434 8, 619.420 9

Ginsenoside Rc

C₅₃H₉₀O₂₂

[M+COOH]^-

-0.2

18.70

1 123.589 5

0.008 6 ± 0.005 1

1 077.659 1, 945.534 9, 783.491 7, 149.048 5

Malonyl ginsenoside Rc

C₅₆H₉₂O₂₅

[M-H]^-

0.2

17.60

1 163.585 5

0.011 2 ± 0.002 8

1 077.591 8, 1 059.580 0

Schisanhenol

C₂₃H₃₀O₆

[M+H]⁺

-0.1

40.01

403.211 5

0.026 9 ± 0.007 9

371.184 7, 340.166 6, 271.257 2, 301.089 8

Schisandrin A^*

C₂₄H₃₂O₆

[M+H]⁺

-0.3

44.06

417.227 2

0.265 1 ± 0.136 7

402.204 1, 386.204 4, 316.130 7, 301.105 5

Schisandrol A^*

C₂₄H₃₂O₇

[M+H]⁺

-0.5

25.67

433.222 1

0.488 4 ± 0.297 2

415.208 4, 400.187 1, 384.193 4, 369.169 5

Gomisin D^*

C₂₈H₃₄O₁₀

[M+H]⁺

-0.8

27.76

531.222 5

0.347 8 ± 0.149 8

401.157 5, 353.136 6, 326.114 7

Benzoylgomisin Q

C₃₁H₃₆O₉

[M+H]⁺

0.1

35.99

553.243 2

0.065 0 ± 0.070 7

453.187 6, 387.177 1, 356.162 0, 343.118 4

Rubrisandrin B

C₂₂H₂₈O₆

[M+H]⁺

0.1

22.71

389.195 9

0.024 2 ± 0.006 6

389.218 9, 357.168 8, 325.135 2, 288.099 9

Gomisin N

C₂₃H₂₈O₆

[M+H]⁺

0.2

45.82

401.195 9

0.039 2 ± 0.029 8

386.171 2, 300.100 6, 285.074 8, 242.094 5

Schisandrin B^*

C₂₃H₂₈O₆

[M+H]⁺

-0.4

46.25

401.195 9

0.515 3 ± 0.164 1

386.170 4, 370.167 7, 300.097 2, 285.074 0

Schisandrol B^*

C₂₃H₂₈O₇

[M+Na]⁺

0.5

29.37

417.190 8

0.013 6 ± 0.007 1

399.158 4, 369.167 0, 368.160 2, 353.139 1

Gomisin S

C₂₃H₃₀O₇

[M+Na]⁺

0.2

20.15

441.188 4

0.097 4 ± 0.086 1

369.171 1, 337.142 3, 323.129 5, 301.105 3

Schisantherin C

C₂₈H₃₄O₉

[M+H]⁺

-0.2

39.20

515.227 6

0.025 7 ± 0.010 2

437.147 9, 415.175 4, 385.161 3, 371.147 9

Angeloygomisin H^*

C₂₈H₃₆O₈

[M+Na]⁺

0.1

34.22

501.248 3

0.015 9 ± 0.009 4

483.231 6, 401.196 6, 370.177 6, 337.146 6

Schisphenlignan A

C₂₉H₃₀O₉

[M+H]⁺

-4.2

29.87

523.196 3

0.041 6 ± 0.019 7

423.139 3, 383.143 7, 352.129 7, 341.102 6

Angeloylgomisin Q

C₂₉H₃₈O₉

[M+Na]⁺

0.0

35.99

553.240 8

0.066 3 ± 0.071 7

453.192 4, 431.192 4, 387.184 2, 358.140 9

Benzoylgomisin P

C₃₀H₃₂O₉

[M+H]⁺

-1.8

38.11

537.211 9

0.041 4 ± 0.021 2

437.163 2, 415.169 5, 371.149 0, 340.129 8

Target	Binding energy / kcal·mol^-1
FXR	-6.2	-6.0	-7.5
CYP7A1	-7.2	-6.5	-8.4
BSEP	-6.5	-8.1	-6.1
OATP1B1	-6.3	-7.4	-9.4

Target

Binding energy / kcal·mol^-1

Ginsenoside Rb1

Schisandrin A

Target inhibitor

FXR

-6.2

-6.0

-7.5

CYP7A1

-7.2

-6.5

-8.4

BSEP

-6.5

-8.1

-6.1

OATP1B1

-6.3

-7.4

-9.4