Evidence and possible mechanism of Scutellaria baicalensis and its bioactive compounds for hepatocellular carcinoma treatment

Figures & data

Figure 1. Potential BAI, BAE, and WOG action mechanisms in HCC treatment. BAE, BAI, and WOG affected cell apoptosis by inhibiting the expression of Bcl-2/Bax and migration by activating the ER stress and ROS pathway. BAE starts the effect of cell-cycle regulation by inhibiting the expression and function of cell-cycle genes, including CyclinE, CyclinD1, CyclinB1, CyclinA2, and CDK. BAE, BAI, and WOG induce autophagy, cell cycle, and necrosis by PI3K/Akt/mTOR, Hippo, and Nf-KB pathways. BAI and BAE inhibited migration by decreasing adhesion molecule release. Abbreviation: BAI, baicalin, BAE, baicalein, WOG, Wogonin.

Figure 2. Literature search and study inclusion.

Table 1. Meta-analysis of clinical outcomes.

Study or subgroup	Experimental		Control		Risk Ratio
	Events	Total	Events total		M-H fixed 95% Cl	p value
CHM compound based S. baicalensis
ORR
Wang, et al.. 2016	18	30	9	30	2.00 [1.08, 3.72]	_
Li, et al.. 2019	38	56	27	56	1.41 [1.02, 1.95]	_
Liang, et al.. 2020	15	40	5	40	3.00 [1.20, 7.47]	_
Liu, et al.. 2013	6	32	4	32	1.50 [0.47, 4.82]	_
Wang, et al.. 2022	30	44	20	44	1.50 [1.02, 2.20]	_
Zhang, et al.. 2018	31	46	23	46	1.35 [0.95, 1.92]	_
Total (95% Cl) I^2 = 0%					1.57 [1.30, 1.90]	p < 0.00001
KPS score
Liu, et al.. 2013	30	32	20	32	1.50 [1.13, 1.99]	_
Zhang, et al.. 2018	35	46	30	46	1.17 [0.89, 1.52]	_
Total (95% Cl) I^2 = 38%					1.32 [1.03, 1.69]	p = 0.03
Adverse events
Wang, et al.. 2016	8	30	17	30	0.47 [0.24, 0.92]	_
Li, et al.. 2019	1	56	1	56	1.00 [0.06,15.59]	_
Wang, et al.. 2022	5	60	9	60	0.56 [0.20, 1.56]	_
Zhang, et al.. 2018	14	46	21	46	0.67 [0.39, 1.14]	_
Total (95% Cl) I^2 = 0%					0.58 [0.40, 0.86]	p = 0.006

Table 2. Meta-analysis of preclinical outcome in vivo studies.

	Experimental			Control			Std. mean difference
Study or subgroup	Mean	SD	Total	Mean	SD	Total	IV. Random. 95% Cl	P value
Weight of tumor
Baicalein
Cui, 2012-H	0.61	0.18	10	1.59	0.28	10	−3.99 [–5.62, −2.35]	_
Cui, 2012-M	0.88	0.24	10	1.59	0.28	10	−2.61 [–3.87, −1.35]	_
Cui, 2012-L	1.03	0.37	10	1.59	0.28	10	−1.63 [–2.68, −2.59]	_
Chiu, 2011-M	0.3	0.09	8	1.25	0.05	8	−12.34 [–17.36, −7.32]	_
Chiu, 2011-H	0.28	0.1	8	1.25	0.05	8	−11.60 [–16.33, −6.87]	_
Chiu, 2011-L	0.53	0.11	8	1.25	0.05	8	−7.97 [–11.29, −4.64]	_
Zheng, 2014-H	0.21	0.06	6	0.98	0.15	6	−6.22 [–9.46, −2.98]	_
Zheng, 2014-L	0.4	0.07	6	0.98	0.15	6	−4.57 [–7.08, −2.07]	_
Feng, 2012	0.77	0.88	10	1.01	0.15	10	−0.36 [–1.25, 0.52]	_
Subtotal (95% Cl) I^2 = 89%							−4.80 [–6.66, −2.95]	p < 0.00001
Baicalin
Cui, 2008-H	0.61	0.18	12	1.59	0.28	12	−4.02 [–5.50, −2.54]	_
Cui, 2008-M	0.88	0.24	12	1.59	0.28	12	−2.63 [–3.77, −1.49]	_
Cui, 2008-L	1.03	0.37	12	1.59	0.28	12	−1.65 [–2.60, −0.70]	_
Dong, 2013	0.5	0.03	10	0.73	0.04	10	−6.23 [–8.56, −3.90]	_
Lu, 2020-H	1.91	1.47	10	5.5	3.34	10	−1.33 [–2.32, −0.34]	_
Lu, 2020-M	2.08	1.54	10	5.5	3.34	10	−1.26 [–2.24, −0.28]	_
Lu, 2020-L	2.75	2.93	10	5.5	3.34	10	−0.84 [–1.76, 0.08]	_
Subtotal (95% Cl) I^2 = 81%							−2.28 [–3.26, −1.30]	p < 0.00001
Huangqin
Cheng, 2018	0.64	0.32	10	1.17	0.36	10	−1.49 [–2.51, −0.47]	_
Li-2, 2016-M	1.03	0.46	12	1.7	0.56	12	−1.26 [–2.15, −0.37]	_
Li-1, 2016-M	1.13	0.64	10	1.77	0.41	10	−1.14 [–2.10, −0.18]	_
Li-2, 2016-L	1.35	0.39	12	1.7	0.56	12	−0.70 [–1.53, 0.13]	_
Li-2, 2016-H	1.39	0.31	12	1.7	0.56	12	−0.66 [–1.49, 0.16]	_
Li-1, 2016-H	1.48	0.63	10	1.77	0.41	10	−0.52 [–1.42, 0.37]	_
Li-1, 2016-L	1.48	0.66	10	1.77	0.41	10	−0.51 [–1.40, 0.39]	_
Subtotal (95% Cl) I^2 = 0%							−0.86 [–1.20, −0.53]	p < 0.00001
Wogonin
Xu, 2013-H	0.52	0.18	6	1.64	0.61	6	−2.30 [–3.89, −0.71]	_
Xu, 2013-M	0.82	0.33	6	1.64	0.61	6	−1.54 [–2.90, −0.18]	_
Xu, 2013-L	1.25	0.25	6	1.64	0.61	6	−0.77 [–1.97, 0.42]	_
Subtotal (95% Cl) I^2 = 82%							−1.41 [–2.26, −0.57]	p < 0.00001
Total (95% Cl) I^2 = 87%							−2.14 [-2.70, −1.58]	p < 0.00001
Apoptosis of tumor
Baicalein
Cui, 2012-L	15.3	6.7	10	2.9	0.3	10	2.50 [1.27, 3.74]	_
Cui, 2012-M	24.6	3.1	10	2.9	0.3	10	2.61 [6.06, 12.82]	_
Cui, 2012-H	39.1	4.9	10	2.9	0.3	10	1.63 [6.42, 13.55]	_
Du, 2020-L	15.26	3.87	10	8.79	2.35	10	12.34 [0.83, 3.04]	_
Du, 2020-M	35.78	4.45	10	8.79	2.35	10	11.60 [4.60, 9.93]	_
Du, 2020-H	54.38	5.09	10	8.79	2.35	10	11.01 [7.11, 14.92]	_
Subtotal (95% Cl) I^2 = 91%							6.63 [3.76, 9.50]	p < 0.00001
Baicalin
Dong, 2013	13.6	1.1	10	2.2	1.9	10	7.03 [4.45, 9.62]	_
Subtotal (95% Cl)							7.03 [4.45, 9.62]	p < 0.00001
Total (95% Cl) I^2 = 90%							6.68 [4.07, 9.29]	p < 0.00001
Body weight
Baicalein
Zheng, 2014-L	30.6	1.3	6	31.33	2.08	6	−0.73 [–2.69, 1.23]	_
Zheng, 2014-H	30.51	1.33	6	31.33	2.08	6	−0.82 [–2.80, 1.16]	_
Subtotal (95% Cl) I^2 = 0%							−0.77 [–2.17, 0.62]	p = 0.28
Baicalin
Lu, 2020-L	34.41	5.69	10	35.76	3.96	10	−1.35 [–5.65, 2.95]	_
Lu, 2020-M	34.45	5.1	10	35.76	3.96	10	−1.31 [–5.31, 2.69]	_
Lu, 2020-H	36.27	6.7	10	35.76	3.96	10	0.51 [–4.31,5.33]	_
Subtotal (95% Cl) I^2 = 81%							−0.83 [–3.34, 1.67]	p = 0.51
S. baicalensis
Li-1, 2016-L	31.2	3.9	10	31.9	2.4	10	−0.70 [–3.54, 2.14]	_
Li-1, 2016-M	30.1	2.9	10	31.9	2.4	10	−1.80 [–4.13, 0.53]	_
Li-1, 2016-H	30.7	2.5	10	31.9	2.4	10	−1.20 [–3.35, 0.95]	_
Li-2, 2016-L	34.1	4.2	12	33.9	2.5	12	0.20 [–2.57, 2.97]	_
Li-2, 2016-M	33.8	2.7	12	33.9	2.5	12	−0.10 [–2.18, 1.98]	_
Li-2, 2016-H	34.6	2.0	12	33.9	2.5	12	0.70 [–1.11, 2.51]	_
Yan, 2010	396.41	61.3	23	357.57	74.84	18	38.84 [–3.86, 81.54]	_
Yang, 2021	89.68	3.88	5	92.78	7.33	5	−3.10 [–10.37, 4.17]
Subtotal (95% Cl) I^2 = 6%							−0.41 [–1.32, 0.50]	p = 0.37
Wogonin
Hong, 2020-1	21.32	1.4	6	23.1	1.14	6	−1.78 [–3.22, −0.34]	_
Hong, 2020-2	23.74	1.28	6	23.1	1.14	6	0.64 [–0.73, 2.01]	_
Xu, 2013-1	23.6	2.92	6	25.45	2.07	6	−1.85 [–4.71, 1.01]	_
Xu, 2013-2	24.09	2.21	6	25.45	2.07	6	−1.36 [–3.78, 1.06]	_
Xu, 2013-3	25.08	2.07	6	25.45	2.07	6	−0.37 [–2.71, 1.97]	_
Subtotal (95% Cl) I^2 = 41%							−1.41 [–2.26, −0.57]	p = 0.10
total (95% Cl) I^2 = 0%							−0.61 [–1.16, −0.07]	p = 0.03
Liver index
Baicalein
Zheng, 2014-L	7.41	0.39	6	7.56	0.19	6	−0.45 [–1.60, 0.70]	_
Zheng, 2014-H	7.16	0.41	6	7.56	0.19	6	−1.16 [–2.42, 0.11]	_
Subtotal (95% Cl) I^2 = 0%							−0.77 [–1.62,0.08]	p = 0.08
Baicalin
Dong, 2013	2.98	0.41	10	2.51	0.35	10	1.18 [0.21,2.15]	_
Subtotal (95% Cl)							1.18 [0.21,2.15]	p = 0.02
S. baicalensis
Li-1, 2016-L	8.11	2.04	10	8.84	0.83	10	−0.45 [–1.34, 0.44]	_
Li-1, 2016-M	8.31	1.32	10	8.84	0.83	10	−0.46 [–1.35, 0.43]	_
Li-1, 2016-H	8.2	0.74	10	8.84	0.83	10	−0.78 [–1.70, 0.14]	_
Li-2, 2016-L	6.4	1.39	12	6.48	0.45	12	−0.07 [–0.88, 0.73]	_
Li-2, 2016-M	6.76	0.72	12	6.48	0.45	12	0.45 [–0.36, 1.26]	_
Li-2, 2016-H	6.42	0.36	12	6.48	0.45	12	−0.14 [–0.94, 0.66]	_
Yan, 2010	6.71	0.51	8	8.84	0.53	6	−3.85 [–5.83, −1.86]	_
Subtotal (95% Cl) I^2 = 65%							−0.31 [–0.66, 0.03]	p = 0.07
total (95% Cl) I^2 = 68%							−2.14 [–2.70, −1.58]	p = 0.14
Spleen index
Baicalein
Cui, 2012-L	5.45	0.37	10	5.12	0.28	10	0.96 [0.03, 1.90]
Cui, 2012-M	8.04	0.34	10	5.12	0.28	10	8.98 [5.75,12.21]
Cui, 2012-H	8.53	0.53	10	5.12	0.28	10	7.71 [4.90,10.51]
Zheng, 2014-L	0.85	0.07	6	0.84	0.09	6	0.11 [–1.02, 1.25]
Zheng, 2014-H	0.94	0.01	6	0.84	0.09	6	1.44 [0.11,2.77]
Subtotal (95% Cl) I^2 = 91%							3.34 [1.04, 5.64]	p = 0.004
Baicalin
Lu, 2020-L	9.96	4.36	10	12.07	4.03	10	−0.48 [–1.37, 0.41]
Lu, 2020-M	6.88	2.68	10	12.07	4.03	10	−1.45 [–2.46, −0.44]
Lu, 2020-H	6.61	3.04	10	12.07	4.03	10	−1.46 [–2.48, −0.45]
Subtotal (95% Cl) I^2 = 29%							−1.09 [–1.76, −0.43]	p = 0.001
Huangqin
Li-1, 2016-L	0.85	0.35	10	0.77	0.17	10	0.28 [–0.60, 1.16]
Li-1, 2016-M	0.85	0.23	10	0.77	0.17	10	0.38 [–0.51, 1.27]
Li-1, 2016-H	0.79	0.15	10	0.77	0.17	10	0.12 [–0.76, 1.00]
Li-2, 2016-L	0.54	0.15	12	0.63	0.11	12	−0.66 [–1.49, 0.17]
Li-2, 2016-M	0.54	0.1	12	0.63	0.11	12	−0.83 [–1.67, 0.01]
Li-2, 2016-H	0.58	0.11	12	0.63	0.11	12	−0.44 [–1.25, 0.37]
Yan, 2010	0.38	0.09	12	0.48	0.1	12	−1.01 [–1.87, −0.16]
Subtotal (95% Cl) I^2 = 39%							−0.32 [–0.73, 0.09]	p = 0.12
total (95% Cl) I^2 = 85%							0.30 [–0.39,1.00]	p = 0.39
Caspase-3
Baicalein
Cui, 2012-L	142.54	13.36	10	100.67	4.45	10	4.03 [2.38, 5.67]	_
Cui, 2012-M	197.77	16.93	10	100.67	4.45	10	7.51 [4.77, 10.26]	_
Cui, 2012-H	280.62	28.51	10	100.67	4.45	10	8.45 [5.40, 11.50]
Subtotal (95% Cl) I^2 = 77%							6.45 [3.50, 9.40]	p < 0.0001
Baicalin
Dong, 2013	31.31	6.09	10	20.08	5.01	10	1.93 [0.83, 3.03]	_
Subtotal (95% Cl)							1.93 [0.83, 3.03]	p = 0.00006
S. baicalensis
Lam, 2015	8.32	3.39	5	0.68	0.54	5	2.84 [0.82, 4.87]	_
Yang, 2021	6.28	3.64	5	1.26	0.53	5	1.74 [0.16, 3.32]	_
Subtotal (95% Cl) I^2 = 0%							−0.31 [–0.66, 0.03]	p = 0.00007
Total (95% Cl) I^2 = 83%							−2.14 [–2.70, −1.58]	p < 0.0001
VEGF
Baicalein
Du, 2020-L	38.79	4.13	10	53.85	5.15	10	−3.09 [–4.47, −1.71]
Du, 2020-M	23.84	3.37	10	53.85	5.15	10	−6.60 [–9.05, −4.16]
Du, 2020-H	8.55	4.13	10	53.85	5.15	10	−9.29 [–12.63, −5.96]
Subtotal (95% Cl) I^2 = 86%							−6.09 [–9.71, −2.47]	p = 0.0010
Huangqin
Li-2, 2016-L	91	4	12	100	0.01	12	−3.07 [–4.31, −1.83]
Li-2, 2016-M	89	14	12	100	0.01	12	−1.07 [–1.94, −0.21]
Li-2, 2016-H	47	9	12	100	0.01	12	−8.04 [–10.65, −5.43]
Subtotal (95% Cl) I^2 = 93%							−3.79 [–6.75, −0.82]	p = 0.01
Total (95% Cl) I^2 = 91%							−4.85 [–7.04, −2.66]	p < 0.0001

Table 3. Meta-analysis for Bcl-2, MMP-2, MMP-9, caspase-3, and CyclinD1 (in vitro studies).

	Experimental			Control			Std. Mean Difference
Study or Subgroup	Mean	SD	Total	Mean	SD	Total	IV. Random. 95% Cl	P value
Bcl-2
Baicalein
Cui, 2008	32.21	3.35	3	59.26	4.45	3	−5.70 [–11.43, 0.03]	_
Subtotal (95% Cl)							−5.70 [–11.43, 0.03]	p = 0.05
Wogonin
Liu, 2016-H	0.32	0.02	3	0.99	0.03	3	−21.02 [–41.39, −0.66]	_
Liu, 2016-L	0.88	0.02	3	0.99	0.03	3	−3.45 [–7.15, 0.25]	_
Liu, 2016-M	0.67	0.01	3	0.99	0.03	3	−11.45 [–22.62, −0.28]	_
Subtotal (95% Cl) I^2 = 54%							−4.73 [–8.18, −1.27]	p = 0.007
Total (95% Cl) I^2 = 32%							−4.99 [–7.95, −2.02]	p = 0.001
MMP-2
Baicalein
Chiu, 2011	0.58	0.25	3	0.99	0.12	3	−1.67 [–3.95, 0.60]	_
Subtotal (95% Cl)							−1.67 [–3.95, 0.60]	p = 0.15
S. baicalensis
Park, 2014-H	0.13	0.11	3	0.79	0.01	3	−6.76 [–13.48, −0.04]	_
Park, 2014-L	0.42	0.13	3	0.79	0.01	3	−3.21 [–6.70, 0.28]	_
Subtotal (95% Cl) I^2 = 0%							−3.96 [–7.06, −0.87]	p = 0.01
Wogonin
Liu, 2016-H	0.08	0.01	3	0.99	0.01	3	−72.80 [–143.11, −2.49]	_
Liu, 2016-L	0.38	0.01	3	0.99	0.01	3	−48.80 [–95.95, −1.65]	_
Liu, 2016-M	0.34	0.02	3	0.99	0.01	3	−32.89 [–64.68, −1.09]	_
Subtotal (95% Cl) I^2 = 0%							−42.17 [–66.85, −17.48]	p = 0.0008
Total (95% Cl) I^2 = 62%							−2.69 [–4.52, −0.87]	p = 0.004
MMP-9
Baicalein
Chiu, 2011	0.37	0.13	3	0.99	0.12	3	−3.96 [–8.11, 0.18]	_
Subtotal (95% Cl)							−3.96 [–8.11, 0.18]	p = 0.06
Baicalin
Xiao, 2012-H	21.85	3.41	3	41.48	3.55	3	−4.51 [–9.15, 0.13]	_
Xiao, 2012-L	33.26	4.07	3	41.48	3.55	3	−1.72 [–4.03, 0.59]	_
Subtotal (95% Cl) I^2 = 10%							−2.27 [–4.34, −0.21]	p = 0.03
Total (95% Cl) I^2 = 0%							−2.61 [–4.46, −0.76]	p = 0.006
Caspase-3
Baicalein
Kuo, 2009	0.79	0.05	3	0.19	0.03	3	0.60 [0.53, 0.67]	_
Liang, 2012-H	3.55	0.19	3	0.99	0.01	3	2.56 [2.34, 2.78]	_
Liang, 2012-L	1.5	0.42	3	0.99	0.01	3	0.51 [0.03, 0.99]	_
Liang, 2012-M	2.91	0.52	3	0.99	0.01	3	1.92 [1.33, 2.51]	_
Total (95% Cl) I^2 = 99%							1.40 [0.18, 2.61]	p = 0.02
CyclinD1
Baicalein
Zheng, 2014-H	0.33	0.07	3	1	0.01	3	−0.67 [–0.75, −0.59]
Zheng, 2014-L	0.21	0.1	3	1	0.01	3	−0.79 [–0.90, −0.68]
Subtotal (95% Cl) I^2 = 65%							−0.72 [–0.84, −0.61]	p < 0.00001
Wogonin
Hong, 2020-H	3.99	0.64	3	1.01	0.13	3	2.98 [2.24, 3.72]	_
Hong, 2020-L	2.3	0.4	3	1.01	0.13	3	1.29 [0.81, 1.77]	_
Liu, 2016-H	0.28	0.01	3	1	0.01	3	−0.72 [–0.74, −0.70]	_
Liu, 2016-L	0.47	0.02	3	1	0.01	3	−0.53 [–0.56, −0.50]	_
Liu, 2016-M	0.67	0.01	3	1	0.01	3	−0.33 [–0.35, −0.31]	_
Subtotal (95% Cl) I^2 = 100%							−0.02 [–0.27, 0.22]	p = 0.84
Total (95% Cl) I^2 = 100%							−0.27 [–0.46, −0.07]	p = 0.007

Data availability statement

All authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials