Antidiabetic Potential of Sophora Species: Mechanisms, Bioactive Constituents, and Therapeutic Prospects

Abstract

Diabetes is a major global health concern, and achieving optimal glycemic control remains a challenge for many patients. Despite the availability of current antidiabetic medications, about two-thirds of patients worldwide fail to achieve adequate glycemic control, underscoring the need for novel treatments. Herbal medicine has significantly contributed to drug discovery, and Sophora, a genus in the Fabaceae family, has long been used in traditional medicine. Preclinical studies suggest that various chemical constituents of Sophora exhibit antidiabetic properties. This review summarizes in vitro and in vivo evidence on the antidiabetic effects of Sophora, highlighting its active ingredients and mechanisms of action. A literature search was conducted using Web of Science, Scopus, PubMed, and Google Scholar with the keywords ‘Sophora’, ‘diabetes’, and ‘herbal medicine’. Studies indicate that Sophora reduces fasting glucose in type 1 and type 2 diabetes (T2D) by approximately 33% and 37%, respectively. Additionally, it decreases body weight, improves glucose tolerance, reduces insulin resistance, and enhances lipid profiles in T2D. The antidiabetic mechanisms of Sophora involve the activation of phospholipase C-protein kinase C (PLC-PKC), phosphatidylinositol-3-kinase (PI3K)-Akt (PI3K-Akt), and adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways, leading to enhanced glucose uptake in the skeletal muscle. Furthermore, Sophora activates the PI3K-Akt pathway and inhibits nuclear factor-kappa B (NFκB), thereby reducing hepatic gluconeogenesis and inflammation. Among its active constituents, flavonoids exhibit the most significant antidiabetic activity. While Sophora holds promise for antidiabetic drug development, further preclinical studies assessing sex differences and long-term safety are required before progressing to human clinical trials.

Keywords

Sophora - herbal medicine - type 1 diabetes - type 2 diabetes - Fabaceae

Introduction

Diabetes is a major global health concern and one of the leading causes of death worldwide. In 2021, diabetes contributed to approximately 11.8% of deaths among individuals under the age of 60 [1]. According to the International Diabetes Federation (IDF), an estimated 537 million adults (10.5% of the global population) were living with diabetes in 2021, with projections indicating an increase to 783 million (12.5%) by 2045 [1]. Diabetes is primarily classified into two types: type 1 diabetes (T1D), characterized by insulin deficiency, and type 2 diabetes (T2D), which arises due to insulin resistance and progressive pancreatic β-cell dysfunction [1], [2]. Achieving optimal glycemic control–defined as pre-prandial plasma glucose between 80 and 130 mg/dL, postprandial glucose < 180 mg/dL, and glycosylated hemoglobin (HbA1C) < 7% in non-pregnant adults–is a key goal in diabetes management [3]. However, despite the availability of pharmacological treatments, a significant proportion of patients fail to achieve adequate glycemic control. A systematic review and meta-analysis encompassing randomized clinical trials and observational studies across North America, Europe, and Asia reported that approximately two-thirds of patients with T2D and three-quarters of those with T1D did not meet glycemic targets [4]. Furthermore, as diabetes progresses, oral antidiabetic drugs often become less effective; data from the Hong Kong Diabetes Registry indicate that over half of Chinese T2D patients required insulin therapy within 10 – 20 years of diagnosis [5]. Poor glycemic control significantly increases the risk of microvascular and macrovascular complications, further underscoring the need for novel therapeutic strategies [6].

Given the limitations of current pharmacological treatments, there is growing interest in natural products, particularly herbal medicine, as potential sources of novel antidiabetic agents. Herbal medicine, a key component of traditional medicine [7], has increasingly gained commercialized and scientific attention worldwide [8]. Over the past four decades, approximately 32% of newly approved chemical entities have been derived from natural products [9]. This trend is also evident in the case of diabetes drug development, where nearly 30% (19 out of 63) of approved antidiabetic drugs between 1981 and 2019 originated from natural products [9]. Notable examples include sodium-glucose cotransporter-2 (SGLT2) inhibitors such as dapagliflozin and canagliflozin, which are synthetic analogs of phlorizin [10], a glycoside originally isolated from the bark of the apple tree (Malus domestica) [11]. Similarly, metformin–the first-line drug for T2D management [1]–traces its origins to Galega officinalis L., a traditional European herb from the Fabaceae family [12], [13].

The Fabaceae family comprises 807 accepted genera, among which the genus Sophora includes 62 recognized species [14]. Sophora is predominantly a tropical and warm-temperate genus [14], with wide distribution across Asia, Oceanica, and the Pacific islands [15], [16] and to a lesser extent in Africa [17]. Of the 62 species, more than 15 have a long history in traditional Chinese medicine [15], including the root of Sophora flavescens Ait. [18], the seed of Sophora alopecuroides L. [19], and the root of Sophora tonkinensis Gagnep. [15]. Ethnobotanically, various Sophora species have been employed for treating fever, bacterial infections, heart disease, rheumatism, eczema, colitis, sore throat, acute dysentery, and gastrointestinal hemorrhage [15], [17]. In Thailand, Sophora exigua Craib is traditionally used to enhance postpartum lactation in women with hypogalactia and to alleviate fever [17]. In traditional Korean medicine, the roots of Sophora subprostrata and Sophora mollis are utilized for managing fever, inflammation, peptic ulcers, and cancer [17]. In several regions of China, the dried flowers and flower buds of Sophora japonica L. (known as Flos Sophorae) are used to treat hypertension, coronary artery disease, and diabetes [20]. Furthermore, in Razavi Khorasan province of Iran, Sophora pachycarpa seeds are traditionally used by individuals with diabetes to reduce blood glucose levels [21]. Kushen, a traditional herbal remedy derived from the dried root of Sophora flavescens, is widely used in folk medicine and clinical practice in south China to manage T2D [22], [23]. Preclinical studies indicate that various Sophora species possess antidiabetic properties, including the ability to lower fasting blood glucose levels [21], [22], [23], [24], [25], [26], [27], [28], inhibit SGLT activity [29], and upregulate both the expression and membrane translocation of glucose transporter type 4 (GLUT4), which plays a critical role in glucose uptake in insulin-sensitive tissues [25], [26], [27]. Despite promising preclinical data, Sophora has not yet been evaluated in clinical trials for diabetes treatment. To bridge this gap, this review aims to summarize and critically assess the available preclinical evidence regarding the antidiabetic effects of Sophora, its mechanisms of action, and its active phytochemicals. Additionally, we highlight the potential challenges and future research directions necessary for advancing Sophora-based therapies from preclinical models to clinical applications.

Search Strategy

This narrative review was conducted by systematically searching the Web of Science, Scopus, PubMed, and Google Scholar databases to identify relevant studies on the antidiabetic effects of Sophora, its underlying mechanisms, and its bioactive chemical constituents. The literature search covered publications up to January 2025. The primary keywords used included “Sophora”, “diabetes”, and “herbal medicine”. Additionally, the reference lists of the retrieved articles were examined to identify further relevant studies. Only studies published in English were included. After screening titles, abstracts, and full texts for relevance, 43 studies were selected for review.

Evidence for the Antidiabetic Effect of Sophora

Preclinical studies suggest that Sophora exerts beneficial metabolic effects in diabetes. As summarized in [Table 1] and [Table 2], animal studies indicated that Sophora administration reduces fasting blood glucose in both T1D and T2D models. In addition, it has been shown to improve body weight, serum insulin, insulin resistance, glucose tolerance, and lipid profiles in T2D animal models. These findings highlight the potential of Sophora as a complementary or alternative approach to diabetes management.

Table 1 Effect of Sophora on body weight, food intake, and metabolic parameters in rodents with type 1 diabetes (T1D).

Animal			Plant			Intervention			Outcomes
Species	Initial body weight (g)	T1D model	Sophora species	Part of plant	Extract	Dose (mg/kg)	Route	Duration (days)	Fasting blood glucose	Body weight change	Food intake	Liver glycogen	Reference
a All studies were conducted on male rodents; b Not specified fasting state; ↑, increase; ↓, decrease; ↔, no change. *p < 0.05 compared to the untreated diabetic group; NR: not reported
Mice a	25 – 30	STZ, 200 mg/kg	S. pachycarpa	Seed	Ethanolic (80%)	250	Gavage	40	↓*	NR	NR	NR	[21]
Mice	20 – 22	STZ, 80 mg/kg	S. japonica	NR	Total flavonoids	150, 300, 600	Gavage	30	↓*	NR	NR	↑*	[31]
Rats	190 – 210	STZ, 45 mg/kg	S. japonica	Flower	Ethanolic (80%)	50, 100	Oral	28	↔ b	↔	↔	NR	[30]

Table 2 Effect of Sophora on body weight and metabolic parameters in rodents with type 2 diabetes (T2D).

Animal		T2D model	Plant			Intervention			Outcome										Reference
Species	Age (weeks)		Sophora species	Part of plant	Extractb	Route	Duration (days)	Dose (mg/kg)	Body weight	Fasting blood glucose	Serum insulin	Serum NEFA	HOMA-IR	GTT	Serum TG	Serum TC	Serum LDL-C	Serum HDL-C
a All studies were conducted on male rodents; b F, flavonoid-rich; E, ethyl acetate, ↑, increase; ↓, decrease; ↔, no change. *p ≤ 0.05, **p ≤ 0.01, and ***p ≤ 0.001 compared to the untreated diabetic group, respectively; GTT: glucose tolerance test; HDL-C: high-density lipoprotein cholesterol; HFD: high-fat diet; HOMA-IR: homeostasis model assessment of insulin resistance; LDL-C: low-density lipoprotein cholesterol; NEFA: non-esterified fatty acid; STZ: streptozotocin; TC: total cholesterol; TG; triglyceride; NR: not reported
Mice a	8	KK-Ay	S. davidii	Root	F	Gavage	28	60	↓**	↓***	↔	↓*	↓***	↑***	↓*	↔	↔	↔	[24]
								120	↓***	↓***	↓**	↓**	↓***	↑***	↓***	↓**	↓*	↑*
Mice	8	KK-Ay	S. tonkinensis	Root	F	Gavage	28	60	↓**	↓***	↓*	↔	NR	↑*	↔	↔	↓**	↔	[25]
								120	↓***	↓***	↓*	↓**	NR	↑*	↓**	↓*	↓*	↔
								240	↓***	↓***	↓***	↓*	NR	↑*	↓***	↓***	↓*	↑***
Mice	65	HFD-STZ	S. alopecuroides	Seed	F	Gavage	28	100	↔	↓***	↔	↔	↓***	↑***	↓*	↔	↓**	↔	[26]
								200	↔	↓***	↓**	↔	↓***	↑***	↓***	↓**	↓***	↔
Rats	8 – 10	HFD-STZ	S. flavescens	NR	E	Gavage	56	37.5	↔	↔	NR	NR	NR	NR	↓***	↓*	↓***	↔	[22]
								75	↔	↓**	NR	NR	NR	NR	↓***	↓***	↓***	↔
Rats	8 – 10	HFD-STZ	S. flavescens	Root	E	Gavage	56	37.5	↔	↔	↔	NR	↔	NR	NR	NR	NR	NR	[23]
								75	↑*	↓**	↑*	NR	↓*	NR	NR	NR	NR	NR
Mice	8	KK-Ay	S. flavescens	Root	E	Gavage	21	30	↓**	↓*	↓*	↔	NR	↑*	↔	↓*	↔	↔	[27]
								60	↓***	↓**	↓**	↓*	NR	↑*	↓*	↓*	↓**	↔
								120	↓***	↓***	↓**	↓**	NR	↑*	↓**	↓**	↓***	↑**
Rats	8 – 10	HFD-STZ	S. flavescens	NR	E	NR	120	37.5	NR	↔	NR	NR	NR	NR	NR	NR	NR	NR	[28]
								75, 150	NR	↓*	NR	NR	NR	NR	NR	NR	NR	NR

Type 1 Diabetes

We identified three studies evaluating the effect of Sophora extracts in rodent models of T1D ([Table 1]). All studies were conducted on male rodents, with Sophora ethanolic extracts administered orally via gavage at doses ranging from 50 to 600 mg/kg over a period of 28 – 40 days. One study used S. pachycarpa, while two studies used S. japonica. The plant parts tested included seeds [21], flowers [30], and unspecified plant components [31]. These studies indicate that Sophora significantly decreased fasting glucose in mice by 18 – 60% [21], [31], but no significant glucose-lowering effects were observed in rats [30]. One study reported that Sophora increased liver glycogen levels (36 – 68%) [31], suggesting potential benefits in hepatic glucose storage. No significant effects on body weight or food intake were reported in rats [30], while the other two studies did not assess these parameters. Notably, none of the studies specified the age of the T1D rodents, which is an important consideration for disease progression and metabolic outcomes.

Type 2 Diabetes

Seven studies investigated the antidiabetic effects of Sophora extracts in rodent models of T2D ([Table 2]). Three studies used KK-Ay mice, a spontaneous model of T2D, while four studies induced diabetes using a high-fat diet (HFD) combined with a low dose of STZ (35 mg/kg in rats, and 40 mg/kg for two consecutive days in mice). Most studies used male rodents aged 8 – 10 weeks, with one study examining 65-week-old mice [26]. Extracts tested included ethyl acetate or flavonoid-rich fractions at doses ranging from 30 to 240 mg/kg over 21 – 120 days. Except for one study that did not report the route of administration [28], all other studies used Sophora orally (gavage). The species used included S. flavescens (most commonly studied), S. davidii (Franch.) Skeels, S. tonkinensis, and S. alopecuroides. Most studies utilized the root, with one study testing seeds, while two studies did not specify the plant part used.

Following Sophora administration, studies in T2D mice have reported a 12 – 26% decrease in body weight, while findings in rats were inconsistent. Some studies found no significant body weight changes [22], [26], whereas one study reported an increase [23]. Food intake remained unaffected in two studies on mice [24], [25]; however, five other studies did not report food intake.

Glycemic control improved following Sophora treatment, with fasting glucose levels decreasing by 20 – 30% in rats [22], [23], [28] and 25 – 50% in mice [24], [25], [26], [27]. Specifically, fasting glucose in untreated T2D rats ranged from 471.6 ± 8.6 mg/dL to 532.8 ± 10.3 mg/dL, while Sophora administration reduced these levels to 370.8 ± 7.3 mg/dL (p < 0.05) and 370.8 ± 10.8 mg/dL (p < 0.01), respectively. Similarly, in T2D mice, fasting glucose decreased from 329.4 ± 10.8 mg/dL and 347.4 ± 14.4 mg/dL in untreated animals to 246.6 ± 12.6 mg/dL (p ≤ 0.05) and 172.8 ± 16.2 mg/dL (p < 0.001) after treatment. In addition, Sophora administration led to a 7 – 60% decrease in serum insulin and a 20 – 40% reduction in non-esterified fatty acids (NEFA) in mice [24], [25], [26], [27]. Insulin resistance, measured by using the homeostasis model assessment of insulin resistance (HOMA-IR), declined by ~ 17% in rats [23] and 45 – 65% in mice [24], [26]. Moreover, Sophora enhanced glucose tolerance by 25 – 50% in mice.

Lipid profile improvements were also observed following Sophora treatment. Serum triglyceride (TG) decreased by 20 – 60%, total cholesterol (TC) by 20 – 40%, and low-density lipoprotein-cholesterol (LDL-C) by 10 – 50%, while high-density lipoprotein-cholesterol (HDL-C) increased by 50 – 65%. Additional metabolic effects included an increase in liver glycogen storage by 40 – 60%, from 4.7 ± 0.6 mg/g to 6.6 ± 0.6 mg/g and 7.5 ± 0.6 mg/g following administration of 37.5 mg/kg and 75 mg/kg of Sophora, respectively [23]. A 14 – 17% reduction in HbA1C and a ~ 15% decrease in glycosylated serum protein were also reported [22]. Furthermore, Sophora administration was associated with reduced adipocyte size [24] and a decrease in hepatic TG (20 – 51%), TC (16 – 38%) [24], [25], [26], [27], and free fatty acid (FFA, 25 – 45%) [24], [25], [27]. These findings suggest that Sophora exhibits significant antidiabetic and lipid-lowering effects in T2D animal models, warranting further investigation into its therapeutic potential.

Chemical Constituents of Sophora

A comprehensive review identified 370 chemical compounds isolated from various Sophora species, classified into several major categories. Among these, flavonols and flavones (27%), alkaloids (25%), and isoflavonoids (18%) represent the most abundant classes. Other identified compounds include phenolic acids and other phenolic compounds (8%), stilbene oligomers (6%), pterocarpans (5%), chalcones (4%), chromones (1%), coumarins (1%), and benzofuran derivatives (1%), as well as sterol and steroid glucosides (1%) [17]. Several of these compounds exhibit antidiabetic properties ([Fig. 1 ]), particularly those belonging to the flavonoid, alkaloid, stilbene oligomer, pterocarpan, benzofuran derivative, and chalcone groups. Notable bioactive alkaloids include oxymatrine, matrine, and aloperine [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]. Among stilbene oligomers, davidiol E and F have shown potential antidiabetic effects [42]. Pterocarpans such as maackiain and variabilin [29], [43], [44], benzofuran derivatives like (+)-lirioresinol-A, shandougenine A, and shandougenine B [42], and the chalcone such as kuraridin [29], [44], [45] have also demonstrated beneficial metabolic effects. Flavonoids, a predominant group in Sophora, contribute significantly to its antidiabetic activity and can be further classified into five subgroups. Flavanones, including sophoraflavanone G, davidone A – E, and kushenol A, B, E, and T, have been identified as active compounds [29], [44], [45], [46], [47], [48]. Flavonols such as tamarixetin and kaempferol have demonstrated glucose-lowering effects [49]. Isoflavones, including griffonianone H, isoluteolin, formononetin, and cajanin, have shown potential in improving insulin sensitivity [29], [42], [47], [49]. Flavanonols, including kushenol N, K, and L, have been linked to glucose metabolism regulation [29], [48], while flavones such as acacetin [47] and rutin [49] have been associated with antidiabetic effects.

Fig. 1 Chemical constituents of Sophora with antidiabetic effects. SGLT, sodium-dependent glucose transporter. Created with BioRender.com [rerif].

As summarized in [Table 3] [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [43], [46], [50], [51], [52], [53] and [Table 4] [29], [36], [38], [39], [42], [44], [45], [47], [48], [49], [54], [55], [56], preclinical studies using animal models and human-derived cell cultures indicate that these compounds exert antidiabetic effects through multiple mechanisms. These include lowering blood glucose levels, improving insulin resistance, reducing gluconeogenesis, enhancing glucose uptake, stimulating the incretin effect, inhibiting the α-glucosidase enzyme, which slows carbohydrate absorption, and inhibiting SGLT, thereby promoting glucose excretion. These findings suggest that Sophora and its bioactive compounds hold significant promise for diabetes management. However, further clinical investigations are required to validate their efficacy and safety in humans.

Table 3 Antidiabetic effects of chemical constituents of Sophora in in vivo animal studies.

	Flavonoids	Alkaloids	Pterocarpans
↑, increase; ↓, decrease; ↔, no change; GLP-1: glucagon-like peptide-1; NR: not reported. We found no in vivo animal study to address the antidiabetic effects of other chemical constituents of Sophora, including stilbene oligomers, benzofuran derivatives, and chalcones.
Blood glucose concentration	↓ [46]	↓ [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [50], [51], [52]; ↔ [53]	↓ [43]
Serum insulin concentration	↓ [46]	↑ [32], [34], [37]; ↔ [35], [53]; ↓ [38], [39], [41]	↑ [43]
Insulin resistance	NR	↓ [32], [35]	↓ [43]
Insulin-positive cells in pancreatic islet	NR	↑ [38]	NR
Glucose uptake	NR	↑ [32], [38]	NR
Incretin effect (GLP-1)	NR	↑ [32], [39]	NR
Gluconeogenesis	NR	↓ [36]	NR

Table 4 Antidiabetic effects of chemical constituents of Sophora in in vitro human and animal studies.

	Flavonoids	Alkaloids	Stilbene oligomers	Pterocarpans	Benzofuran derivatives	Chalcones
↑, increase; ↓, decrease. NR: not reported; GLP-1: glucagon-like peptide-1; SGLT: sodium-dependent glucose transporter
SGLT inhibition	↑ [29], [56]	NR	NR	↑ [29]	NR	↑ [29]
α-Glucosidase inhibition	↑ [44], [45], [48], [54]	NR	NR	↑ [44]	NR	↑ [44], [45]
Glucose uptake	↑ [42], [47], [49], [54]	↑ [36], [38]	↑ [42]	NR	↑ [42]	NR
Insulin resistance	↓ [55]	NR	NR	NR	NR	NR
Gluconeogenic enzyme activity	NR	↓ [36]	NR	NR	NR	NR
Incretin effect (GLP-1)	NR	↑ [39]	NR	NR	NR	NR

Antidiabetic Mechanisms of Sophora

The antidiabetic effects of Sophora have primarily been investigated in the skeletal muscle, liver, and white adipose tissue (WAT). Studies in T2D mice, T2D rats, L6 cells, and C2C12 myotubes [54] indicate that Sophora enhances glucose uptake, improves insulin sensitivity, and regulates lipid metabolism through multiple signaling pathways.

Skeletal Muscle

Experimental evidence suggests that Sophora activates phospholipase C (PLC)-protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt), and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways in skeletal muscle. This activation leads to increased GLUT4 mRNA and protein expression, enhanced GLUT4 translocation from the cytoplasm to the cell membrane [24], [25], [26], [27], [32], [38], [42], [47], and greater glucose uptake [54]. In addition, Sophora increases glycogen content [32] and decreases TC, TG, and FFA [25], [27] in the skeletal muscle of T2D rodents.

As shown in [Fig. 2], aloperine–an alkaloid component of Sophora–binds to its Gq-coupled G-protein coupled receptor (GPCR) in L6 cells, triggering PLC activation. This reaction converts phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 interacts with its receptor in the sarcoplasmic reticulum (SR), leading to an increase in calcium ion (Ca²⁺) release. Elevated intracellular Ca²⁺ and DAG activate PKC, which facilitates GLUT4 translocation to the plasma membrane [38]. A flavonoid-rich extract (FRE) from S. alopecuroides seeds also promotes GLUT4 translocation by activating the PKC pathway [26]. Both aloperine and FRE from S. alopecuroides seeds increase PKC phosphorylation in the skeletal muscle of T2D rodents and L6 cells [26], [38]. Furthermore, FRE from S. alopecuroides seeds upregulates PKC-dependent GLUT4 mRNA expression in L6 cells [26] and increases PKC-dependent GLUT4 protein expression in T2D rodents and L6 cells [26], [38]. Aloperine also enhances GLUT4 translocation via the PI3K-Akt pathway, stimulating Akt phosphorylation and activation in the skeletal muscle of T2D rats and L6 cells [38]. This suggests that aloperine may mimic some insulin actions.

Fig. 2 Effects of Sophora on glucose uptake in the skeletal muscle. Sophora in the skeletal muscle activates the PLC-PKC, PI3K-Akt, and AMPK signaling pathways, increasing GLUT4 mRNA and protein expression and GLUT4 translocation from the cytoplasm to the plasma membrane. Akt: protein kinase B; AMPK: adenosine monophosphate (AMP)-activated protein kinase; Ca²⁺: calcium ion; DAG: diacylglycerol; GLUT4: glucose transporter type 4; GPCR: G-protein coupled receptor; INSR: insulin receptor; IP₃: inositol-1,4,5-trisphosphate; IP₃R: IP₃ receptor; P-Akt: phosphorylated Akt; P-AMPK: phosphorylated AMPK; PIP₂: phosphatidylinositol-4,5-bisphosphate; PI3K: phosphatidylinositol-3-kinase; PKC: protein kinase C; PLC: phospholipase C; SR: sarcoplasmic reticulum. Created with BioRender.com [rerif].

Another critical mechanism by which Sophora promotes GLUT4 translocation is through the AMPK pathway. Flavonoid-rich extracts from the roots of S. davidii and S. tonkinensis have been shown to phosphorylate and activate AMPK, leading to GLUT4 translocation in T2D mice and L6 cells [24], [25]. Additionally, FRE from S. davidii roots enhances GLUT4 protein expression via the AMPK pathway [24].

The involvement of these pathways is further supported by pharmacological inhibition studies. For example, a PKC inhibitor (Gö6983) blocks GLUT4 mRNA expression, protein expression, and translocation induced by aloperine and FRE from S. alopecuroides seeds in L6 cells [26], [38]. However, it does not inhibit GLUT4 translocation induced by FRE from S. davidii roots in L6 cells [24], suggesting that different plant extracts may act through distinct pathways. A PI3K inhibitor (wortmannin) inhibits GLUT4 translocation induced by aloperine [38] but has no effect on translocation stimulated by FRE from S. davidii roots [24], S. tonkinensis roots [25], and S. alopecuroides seeds [26] in L6 cells. An AMPK inhibitor (compound C) inhibits GLUT4 protein expression [24] and translocation [24], [25] induced by flavonoid-rich extracts from S. davidii and S. tonkinensis roots but does not affect aloperine [38] or FRE from S. alopecuroides seeds [26] in L6 cells.

Several other Sophora constituents have been shown to enhance GLUT4 translocation and glucose uptake [54] in L6 cells and C2C12 myotubes [54], though their precise mechanisms remain unclear. These include ethyl acetate extract from the root of S. flavescens [27], isolated compounds from S. davidii roots, such as davidiol E, davidiol F, shandougenine A & B, (+)-lirioresinol-A, isoluteolin, griffonianone H, davidone A – E, leachianone A, brosibacutin C, and acacetin [42], [47], and sophoricoside, an isoflavone glycoside isolated from S. japonica [54].

In summary, these findings collectively demonstrate that Sophora and its bioactive constituents improve insulin sensitivity and enhance glucose uptake in skeletal muscle by activating multiple signaling pathways, including PLC-PKC, PI3K-Akt, and AMPK. This makes Sophora a promising candidate for developing novel antidiabetic therapies.

Liver

Experimental studies in T2D mice, T2D rats, and HepG2 cells suggest that Sophora exerts beneficial effects on the liver by deactivating nuclear factor-kappa B (NFκB) and activating the PI3K-Akt and AMPK signaling pathways. These mechanisms lead to reduced inflammation, decreased gluconeogenesis, lower lipid accumulation, and increased glycogen synthesis. Furthermore, histopathological observations indicate that Sophora promotes structural recovery in damaged liver tissue.

Sophora reduces hepatic inflammation by suppressing NFκB signaling in hepatocytes. As shown in [Fig. 3], under normal conditions, NFκB is bound to its inhibitor (inhibitor of kappa B, IKB) and remains in the hepatocyte cytoplasm. However, phosphorylation of IKB kinase (IKK) triggers IKB degradation, allowing NFκB to translocate into the nucleus and promote the expression of inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6). In T2D rat livers, ethyl acetate extract from S. flavescens roots reduces IKK-α and IKK-β phosphorylation, thereby reducing hepatic inflammation [23]. Additionally, oxymatrine decreases the protein expression of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) and interleukin-1β (IL-1β), which are two inflammatory mediators of liver inflammation in T2D mice and palmitic acid-induced HepG2 cells [50].

Fig. 3 Effects of Sophora on inflammation and lipid and glucose metabolism in the liver. Sophora in the liver suppresses NFκB and activates the PI3K-Akt and AMPK signaling pathways, thereby decreasing inflammation, gluconeogenesis, and lipid accumulation and elevating glycogen synthesis. ACC: acetyl-CoA carboxylase; Akt: protein kinase B; AMPK: adenosine monophosphate (AMP)-activated protein kinase; FAS: fatty acid synthase; G6Pase: glucose-6-phosphatase; HMGR: 3-hydroxy-3-methylglutaryl coenzyme A reductase; IKB: inhibitor of kappa B; IKK: inhibitor of kappa B kinase; IL-1β: interleukin-1β; IL-6: interleukin-6; INSR: insulin receptor; IRS-1: insulin receptor substrate-1; NFκB: nuclear transcription factor-kappa B; NLRP3: nucleotide-binding oligomerization domain (NOD)-like receptor protein 3; P-ACC: phosphorylated acetyl-CoA carboxylase; P-Akt: phosphorylated protein kinase B; P-AMPK: phosphorylated AMPK; PDK1: 3-phosphoinositide dependent kinase-1; PEPCK: phosphoenolpyruvate carboxykinase; P-IKB: phosphorylated inhibitor of kappa B; P-IKK: phosphorylated inhibitor of kappa B kinase; PIP2: phosphatidylinositol-4,5-bisphosphate; PIP3: phosphatidylinositol-3,4,5-trisphosphate; P-IRS-1: phosphorylated insulin receptor substrate-1; PI3K: phosphatidylinositol-3-kinase; PTEN: phosphatase and tension homology; S: Sophora; SREBPs: sterol regulatory element-binding protein isoforms; TC: total cholesterol; TG: triglyceride; TNF: tumor necrosis factor. Created with BioRender.com [rerif].

Beyond its anti-inflammatory effects, Sophora amplifies and, at some points, mimics the insulin signaling pathway in the hepatocytes, reducing gluconeogenesis and increasing glycogen synthesis. In T2D ratʼs livers, ethyl acetate extract from S. flavescens roots upregulates insulin receptor substrate-1 (IRS-1), PI3K, and Akt protein expression [23], amplifying insulin signaling. Similarly, ethyl acetate extract from the roots of S. flavescens [23], aloperine [38], and oxymatrine [35], [36] phosphorylate and activate Akt, leading to the suppression of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), in T2D rat livers and HepG2 cells [36]. This suppression is reversed by the Akt inhibitor (MK-2206), confirming that the PI3K-Akt pathway plays a role in this process [36]. Furthermore, oxymatrine suppresses mRNA and protein expression for phosphatase and tension homology (PTEN, a negative regulator of insulin signaling, in T2D rat livers [35], while both ethyl acetate extract from the root of S. flavescens and oxymatrine enhance hepatic glycogen storage [23], [32], [35].

Sophora also regulates lipid metabolism through the AMPK pathway. Studies show that flavonoid-rich extracts from S. davidii [24] and S. tonkinensis [25] roots, ethyl acetate extract from S. flavescens [27] roots, and sophoricoside [54] activate AMPK phosphorylation in the livers of T2D mice and oleic acid-induced HepG2 cells [54]. Once activated, AMPK phosphorylates acetyl-CoA carboxylase (ACC) [24], [57], which promotes fatty acid (FA) oxidation and inhibits FA synthesis [58]. In addition, sophoricoside further reduces lipid synthesis by downregulating key lipogenic regulators, including sterol regulatory element-binding protein (SREBP) (a transcription factor that controls the synthesis of cholesterol and fatty acids), fatty acid synthase (FAS), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR)–a key enzyme in Cholesterol biosynthesis [54]. As a result, sophoricoside decreases lipid accumulation in oleic-acid-induced HepG2 cells [54]. Moreover, sophoricoside and oxymatrine [50] decrease intracellular total lipids [54], TG [50], [54], and TC [50], [54] in palmitic-acid- [54] and oleic-acid-induced [50] lipid accumulation models. Evidence supporting this notion is that compound C, an AMPK inhibitor, inhibits the TC- and TG-lowering effect of sophoricoside in HepG2 cells [54] ([Fig. 3]).

In addition to these metabolic benefits, Sophora promotes liver tissue repair in T2D. Studies indicate that flavonoid-rich extracts from S. davidii and S. tonkinensis roots, ethyl acetate extract from S. flavescens roots, FRE from S. alopecuroides seeds, aloperine, and oxymatrine help restore hepatic structure by improving hepatic steatosis [24], [25], [26], [27], [38], [50], reducing lipid droplet accumulation [23], [24], [38], [50], reversing hepatocellular necrosis [32], reversing vacuolization [25], [32], preventing karyopyknosis and fibrosis [36], restoring intracellular spaces, and decreasing edema [35]. Additionally, oxymatrine suppresses protein expression of transforming growth factor-β1 (TGF-β1) and collagen I, both of which are markers of hepatic fibrosis in T2D mice and palmitic acid-induced HepG2 cells [50].

In summary, Sophora and its bioactive constituents offer a multifaceted approach to improving liver health in T2D by reducing inflammation, suppressing gluconeogenesis, enhancing glycogen storage, and regulating lipid metabolism. In addition, Sophora aids in liver tissue repair, making it a promising therapeutic candidate for preventing and treating hepatic complications associated with T2D. However, further studies are needed to fully elucidate the underlying molecular mechanisms.

White Adipose Tissue

Experimental studies in T2D mice [24], [26] and rats [38] suggest that Sophora exerts beneficial effects on WAT by modulating key metabolic signaling pathways. Specifically, Sophora phosphorylates and activates Akt [38] and AMPK [24], leading to enhanced glucose uptake through increased GLUT4 protein expression [24], [26], [38] in WAT. These effects contribute to improved insulin sensitivity and glucose metabolism in adipose tissue.

In addition to its effects on glucose uptake, Sophora influences lipid metabolism by activating AMPK, which subsequently phosphorylates and deactivates ACC [24], a key regulator of fatty acid metabolism. The inhibition of ACC leads to increased FA oxidation and decreased FA synthesis, thereby reducing lipid accumulation in WAT. Furthermore, Sophora downregulates the mRNA [59] and protein [24], [26] expression of PPARγ in WAT of T2D mice [24], [26] and C3H10T1/2 mesenchymal stem cells [59]. Since PPARγ is highly expressed in adipose tissue and plays a crucial role in adipogenesis [60], its downregulation by Sophora inhibits adipocyte differentiation and lipid accumulation induced by adipogenic stimuli in C3H10T1/2 mesenchymal stem cells and 3 T3-L1 cells [59]. Sophora also decreases adipocyte size [24], [26] in the WAT of T2D mice [24], [26], which is significant as enlarged adipocytes are associated with insulin resistance, chronic inflammation, and metabolic dysfunction. This suggests that Sophora may improve overall adipose tissue function by promoting healthier adipocyte morphology and metabolic activity.

Although the underlying mechanisms are not yet fully elucidated, these findings suggest that Sophora and its bioactive constituents have the potential to enhance glucose and lipid homeostasis in WAT, one of the primary insulin-sensitive tissues in the human body. Further research is needed to confirm these effects and explore their therapeutic implications for metabolic disorders such as T2D.

Other Mechanisms

Beyond its effects on glucose uptake, lipid metabolism, and inflammation, Sophora exhibits additional antidiabetic properties. Studies conducted in rats and mice with T2D, STC-1 cells, COS-1 cells, and Chinese hamster ovary (CHO) cells indicate that Sophora inhibits SGLT activity [29], [56] and α-glucosidase enzyme activity [44], [45], [48], [54], two key targets in diabetes treatment. Sophora also stimulates the incretin effect [32], [39], which enhances insulin secretion and helps maintain postprandial glucose control. These mechanisms further highlight the potential of Sophora in managing diabetes through multiple biological pathways.

Conclusion and Future Perspectives

This review aimed to summarize the available preclinical evidence on the antidiabetic effects of Sophora species, thereby laying the groundwork for future clinical investigations. Based on the current findings, Sophora appears to be a promising candidate for the development of novel antidiabetic therapies, particularly for T2D. Animal studies suggest that Sophora exerts its antidiabetic effects through two primary mechanisms ([Fig. 4]). First, it reduces circulating glucose levels (approximately 33% in T1D and 37% in T2D) and improves glucose tolerance. Second, it enhances insulin secretion and mitigates insulin resistance (by ~ 48%), likely through improvements in lipid profiles, reductions in hepatic inflammation, enhancement of incretin activity, and promotion of weight loss (by ~ 18%).

Fig. 4 An overview of the antidiabetic effects of Sophora. HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglyceride. Created with BioRender.com [rerif].

Despite promising preclinical data, several critical issues must be addressed prior to initiating clinical trials with Sophora-derived compounds in diabetic patients. First, long-term safety studies are essential and should be conducted in both male and female animals across varying durations of treatment to ensure the absence of systemic toxicity. While ethnobotanical use supports the therapeutic potential of Sophora, no systematic evaluation of its safety or efficacy in diabetic patients has been conducted to date. Although a few reports have indicated the need for controlled trials [18], [19], [20], adverse effects associated with S. alopecuroides L., including dizziness, headache, nausea, vomiting, palpitations, irritability, and pallor, have been documented [19]. Furthermore, the Chinese Food and Drug Administration advises against the use of S. japonica L. during pregnancy [20], underscoring the necessity for safety screening in vulnerable populations. Second, there is a notable sex bias in preclinical studies, as all existing investigations on the antidiabetic effects of Sophora have been conducted exclusively in male animals. This contradicts the NIH mandate for sex inclusion in preclinical research [61], [62], limiting the generalizability of the findings.

In conclusion, Sophora exhibits strong potential as a natural therapeutic agent for T2D by targeting multiple pathogenic mechanisms, including hyperglycemia, insulin resistance, dyslipidemia, and inflammation. However, before progressing to human trials, further preclinical studies are necessary to address outstanding concerns related to safety, sex-specific effects, and optimal dosing. Moreover, given the incomplete phytochemical and pharmacological characterization of all Sophora species, additional research is warranted. The present review provides a rationale for conducting well-designed controlled clinical trials to evaluate Sophora as a novel source for antidiabetic drug development.

Contributorsʼ Statement

Data collection: A. Ghasemi and M. Mousavi. Design of the study: A. Ghasemi and M. Moridi Farimani. Analysis and interpretation of the data: K. Kashfi and M. Mousavi. Drafting the manuscript: M. Mousavi. Critical revision of the manuscript: A. Ghasemi, K. Kashfi, M. Moridi Farimani, M. Mousavi.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 20 October 2024

Accepted after revision: 28 April 2025

Accepted Manuscript online:
30 April 2025

Article published online:
27 May 2025