Herbal medicine remains a cornerstone in the search for novel drug candidates, offering a wealth of pharmacologically active compounds that have been used for centuries in traditional medicine (He et al., 2024). Notably, approximately 25% of drugs currently utilized in clinical practice are derived from plant-based compounds, underscoring the significance of the plant kingdom as a valuable source for drug discovery (Haque et al., 2024). Among these botanical resources, Caesalpinia sappan has garnered significant attention for its dual role as a traditional medicinal remedy and a natural food coloring agent, with its use dating back to ancient times (Sasarom et al., 2024). C. sappan is rich in diverse secondary metabolites, including flavonoids, saponins, alkaloids, tannins, and phenolics, which have been extensively studied for their therapeutic potential (Chukiatsiri et al., 2024; Sucita et al., 2024). Among its bioactive constituents, brazilin and brazilein have emerged as the most studied compounds, demonstrating potent cytotoxic effects against various tumor cell lines, as well as chemopreventive properties (Jenie et al., 2023). Brazilin, in particular, exhibits a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antibacterial, and hypoglycemic effects. It has also shown promise in addressing complex diseases such as osteoarthritis, Parkinson’s disease, and Alzheimer’s disease (Sugiaman et al., 2024). Additionally, other compounds like cassane diterpenoids and sapanone A have exhibited anti-inflammatory, antimalarial, antimicrobial, antiviral, antihyperglycemic (Su et al., 2024) antioxidant, and anticancer properties (He et al., 2024). The long history of culinary and medicinal applications of C. sappan has inspired a growing body of research aimed at elucidating its pharmacological properties and therapeutic potential. Despite extensive investigations, significant gaps remain in understanding its precise mechanisms of action. To advance the development of C. sappan-based therapeutic agents, this review seeks to provide a comprehensive summary of the current knowledge on the pharmacological properties of C. sappan, highlighting its potential contributions to drug development and addressing the need for further research into its mechanisms of action.

To gather relevant data for this review, articles related to C. sappan published within the last decade were sourced from major academic databases, including PubMed, Scopus, and Web of Science. Search terms were strategically grouped based on descriptors from the DeCS (Health Sciences Descriptors) and Medical Subject Headings (MeSH), with the primary search term being “C. sappan.” The inclusion criteria focused on studies exploring both crude extracts and isolated phytoconstituents of C. sappan that demonstrated significant pharmacological properties. This review is structured to cover C. sappan’s broad therapeutic potential, addressing its antioxidant, anti-inflammatory, anti-infectious, and anticancer properties, along with its effectiveness in treating diseases such as diabetes, cardiovascular conditions, and joint-related disorders.

Herbal medicine has been an integral part of traditional clinical treatment for thousands of years in Korea, China, Japan, and other East Asian countries (Koonrungsesomboon et al., 2024). In recent decades, extensive research has focused on the therapeutic potential of natural antioxidants, particularly those derived from medicinal plants. These natural antioxidants are widely distributed in herbal medicines and exhibit a broad spectrum of biological activities, including anti-cancer, anti-inflammatory, and anti-aging effects (Halliwell, 2024).

The heartwood of C. sappan is the richest source of the plant’s bioactive compounds, although research has also focused on key compounds extracted from its seeds. Phytochemicals from the heartwood are primarily homoisoflavonoids, while those isolated from the seeds are generally classified as diterpenoids. Homoisoflavonoids, which are characterized by the addition of a carbon atom to the skeleton structure of traditional isoflavonoids, are prominent in the Caesalpinia genus. While Sappanin is a common homoisoflavonoid in related species, the rarer brazilin is the key compound of interest in C. sappan (Castelli and López, 2017). Compounds isolated from the seeds of C. sappan typically belong to the diterpenoid class a diverse group of phytochemicals composed of 20 carbon terpenoids formed from four isoprene units. Interest in diterpenoids surged after the approval of the diterpenoid taxane drug, Taxol (derived from Taxus brevifolia), as a first-line treatment for cancer (Yarnell, 2007). The discovery of diterpenoids’ significant biological activity in cancer therapies has expanded interest in their potential medicinal applications, making C. sappan a subject of growing pharmacological interest. This unique combination of bioactive compounds from both heartwood and seeds underlines C. sappan’s versatility and potential for developing novel therapeutic agents across a variety of medical fields. Contributing to this, the toxicity prediction of the C. sappan constituents presented in Table 1 indicates that they mostly have a toxicity class between 4 and 5, with emphasis on Sappanone A with a predicted LD₅₀ of 3,800 mg/kg, and lowest predicted toxicity.

Among the studies highlighted in this review, the heartwood of C. sappan was the most frequently utilized source, with Brazilin emerging as the most extensively researched compound. Brazilin demonstrated potent cytotoxic effects across a wide range of cancer cell lines, while also exhibiting remarkable antioxidant properties. It was particularly effective in shielding non-cancerous cells from oxidative stress, thereby preventing protein denaturation. Beyond its anticancer and antioxidant capacities, Brazilin also displayed significant anti-infectious properties. It was found to combat both common and drug-resistant bacterial strains, as well as viruses, by effectively reducing viral protein R activity. These findings underscore Brazilin’s multifaceted potential as a therapeutic agent with broad-spectrum applications in cancer treatment, infection control, and cellular protection. Sappanone has also been widely investigated in the last decade, showing efficacy as an anti-inflammatory agent, capable of overcoming bacterial resistance and mainly having an effect against different diseases, such as diabetes, cardiovascular disease, asthma and even joint-related disease (Figure 2).

Numerous studies have highlighted the potent antioxidant and anti-inflammatory properties of various compounds isolated from C. sappan, solidifying its role as a promising therapeutic agent, the modulation of these signaling pathways is summarized in Figure 3. Table 2 presents key studies that explored these activities and the underlying mechanisms of action of the isolated compounds. Kim et al. (2014) demonstrated the anti-inflammatory effects of 3-deoxysappanchalcone, a chalcone derived from C. sappan heartwood. This compound exhibited its therapeutic potential by inducing heme oxygenase-1 (HO-1) expression and activating the AKT/mTOR pathway, leading to the inhibition of NO and IL-6 production in LPS-stimulated RAW264.7 cells (Kim et al., 2014). In the same vein, Kim K. J. et al. (2015) also investigated brazilein and found it to effectively suppress inflammatory mediators. By downregulating iNOX and COX2 expression, brazilein reduced pro-inflammatory cytokines and inhibited NF-κB luciferase activity (Kim K. J. et al., 2015). Tewtrakul et al. (2015) identified brazilin as the most potent compound from C. sappan roots, significantly inhibiting NO production in LPS-induced RAW264.7 cells. Sappanchalcone also displayed notable efficacy. Their findings revealed that brazilin also inhibited PGE2 and TNF-α production, suggesting a mechanism involving the downregulation of iNOS, COX-2, and TNF-α (Tewtrakul et al., 2015). In another study, Uddin et al. (2015) found that sappanol and brazilin provided protection against oxidative stress in H₂O₂-induced RGC-5 cells. These compounds effectively reduced A2E photooxidation and lipid peroxidation, improving cell viability while decreasing apoptosis and ROS generation (Uddin et al., 2015). Mueller et al. (2016) isolated five fractions from ethanolic extracts of C. sappan heartwood—episappanol, protosappanin C, brazilin, (iso-) protosappanin B, and sappanol—and evaluated their anti-inflammatory activities. All five compounds inhibited IL-6 and TNF-α secretion in both LPS-stimulated RAW 264.7 cells and IL-1β-stimulated SW1353 cells. Additionally, sappanol enhanced IL-10 secretion, with brazilin showing the strongest anti-inflammatory activity (Mueller et al., 2016). Nirmal and Panichayupakaranant further substantiated the versatile properties of brazilin, demonstrating its antioxidant, antibacterial, and anti-inflammatory effects. Their study revealed brazilin’s ability to perform radical scavenging and prevent denaturation, thereby supporting its role in disease mitigation (Nirmal and Panichayupakaranant, 2015). Wang et al. (2019) provided insights into the neuroprotective role of brazilin, demonstrating its antidepressant and anxiolytic effects in models of H₂O₂-induced oxidative injury in PC12 cells and CMS-induced depression in mice (Wang et al., 2019). Similarly, Zeng et al. (2015) explored the anti-neuroinflammatory potential of Deoxysappanone B, reporting its ability to inhibit NO, PGE₂, TNF-α, IL-6, and ROS production in LPS-induced BV-2 microglia and microglia-neuron co-cultures (Zeng et al., 2015). Wang et al. (2017) highlighted Protosappanin A as an effective anti-neuroinflammatory agent. By inhibiting the production of TNF-α, IL-1β, and suppressing the JAK2/STAT3 pathway, Protosappanin A exhibited strong anti-inflammatory properties in LPS-stimulated BV2 cells (Wang et al., 2017). In their search for natural treatments for chronic obstructive pulmonary disease (COPD), Wang et al. (2023) identified Sappanone A through molecular docking and dynamics analysis as a potent phosphodiesterase 4 (PDE4) inhibitor. In vitro and in vivo studies confirmed its efficacy, with Sappanone A decreasing TNF-α levels, scavenging DPPH radicals, and reducing inflammation in bronchoalveolar lavage fluid (Wang et al., 2023). Lee H. et al. (2015) further corroborated Sappanone A’s anti-inflammatory effects through modulation of the Nrf2/NF-κB pathway. Sappanone A significantly downregulated pro-inflammatory mediators in LPS-stimulated RAW264.7 cells and provided protection against LPS-induced mortality in mice (Lee H. et al., 2015). Liu et al. (2016) examined the effectiveness of Sappanone A in an asthma model, noting reductions in IL-4, IL-5, IL-13, and OVA-specific IgE levels in bronchoalveolar lavage fluid. The treatment also upregulated IFN-γ, reducing airway inflammation and mucus hypersecretion by activating the Nrf2 pathway (Liu et al., 2016).

Table 3 presents a summary of studies directly investigating the antioxidant and anti-inflammatory properties of C. sappan extracts. Pyun et al. (2022) explored the therapeutic effects of aqueous C. sappan heartwood extract on inflamed nasal epithelial cells and an allergic rhinitis model in mice. Their findings demonstrated a significant reduction in ROS production and inhibition of inflammatory mediators induced by IL-4/IL-13 in primary human nasal epithelial cells. The underlying mechanisms involved regulation of the ERK-MAPK and Nrf2/HO-1 signaling pathways, indicating a strong anti-inflammatory and antioxidant response (Pyun et al., 2022). Chen and Zhang (2014) conducted an extensive evaluation of 81 Chinese herbs, including C. sappan, on their ability to modulate inducible nitric oxide synthase (iNOS) activity in LPS/IFNγ-co-stimulated RAW264.7 cells. They reported that the ethanolic extract of C. sappan significantly suppressed NO production, underscoring its anti-inflammatory potential (Chen and Zhang, 2014). Similarly, Pattananandecha et al. (2022) showed that various ethanolic extracts from C. sappan heartwood inhibited NO and iNOS production in RAW264.7 cells wi(th minimal cytotoxicity. In addition, these extracts demonstrated potent inhibition of COX-2 production in HT-29 and LPS/IFN-γ co-stimulated HCT116 cells, reinforcing C. sappan’s role as an anti-inflammatory agent (Pattananandecha et al., 2022). Wan et al. (2019) investigated the neuroprotective potential of C. sappan ethanolic extract using a Rat Middle Cerebral Artery Occlusion (MCAO) Model, bioinformatics analysis, and human bone marrow neuroblastoma (SH-SY5Y) and rat pheochromocytoma (PC12) cells. The study revealed that C. sappan reversed MCAO-induced cerebral injury, inhibited neuronal apoptosis, and mitigated neuroinflammation by reducing neutrophil infiltration, astroglial activation, collagen deposition, and DNA damage/telomere stress. The extract exerted these effects by activating the JAK-STAT and HSP90 signaling pathways, showcasing its multifaceted neuroprotective and anti-inflammatory actions (Wan et al., 2019).

A growing body of research has highlighted C. sappan as a potent anti-infectious agent, effective against a wide range of microorganisms (Tables 4, 5). Seo et al. (2017) demonstrated the strong antitubercular properties of an ethyl acetate fraction derived from the heartwood of C. sappan. The active compound, 3-deoxysappanchalcone, exhibited significant activity against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. Additionally, it displayed partial synergy when combined with streptomycin and ethambutol, offering a promising avenue for tuberculosis treatment (Seo et al., 2017). In a study by Arjin et al. (2022), the bioactive compound brazilin from C. sappan was shown to inhibit viral infections, particularly in porcine reproductive and respiratory syndrome. Molecular docking predicted that brazilin had the highest binding energy with the receptor cysteine-rich domain 5 (SRCR5) of CD163. Brazilin effectively inhibited viral infection in MARC-145 cells, suggesting a potential application in antiviral therapies (Arjin et al., 2022). Puttipan et al. (2018) explored the antibacterial effects of the ethanolic extract and brazilin from C. sappan on Streptococcus mutans, a key pathogen in dental biofilm formation. Both the extract and brazilin demonstrated dose-dependent inhibition of biofilm formation. However, it was noted that brazilin exhibited higher cytotoxicity in fibroblasts, highlighting the need for careful dosage consideration in therapeutic applications (Puttipan et al., 2018). Nirmal and Panichayupakaranant (2014) investigated the antibacterial efficacy of brazilin and a brazilin-rich extract against anaerobic and aerobic bacteria. Their study revealed that Propionibacterium acnes was particularly susceptible to both treatments, with brazilin showing superior effectiveness, reinforcing its potential as an antimicrobial agent (Nirmal and Panichayupakaranant, 2014). Zuo et al. (2014) studied the synergistic effects of combining aminoglycoside antibiotics with C. sappan compounds, including brazilin, brazilein, and sappanone, against methicillin-resistant Staphylococcus aureus (MRSA). Among the compounds, brazilin displayed the strongest synergistic effect when used in combination with aminoglycosides, presenting a promising strategy to combat antibiotic resistance (Zuo et al., 2014). Jaisi et al. (2021) investigated the ethanolic extracts of twelve Thai medicinal herbs, including C. sappan, and their inhibitory effects on HIV-1 Viral Protein R (Vpr). Both the ethanolic extract and the isolated brazilin exhibited significant anti-Vpr activity, suggesting their potential role in HIV treatment strategies (Jaisi et al., 2021). In the realm of antimalarial research, Ma et al. (2015) reported the antimalarial and antiproliferative activities of compounds from C. sappan seeds. Two cassane diterpenes, Caesalsappanin G and H, were found to be highly effective against the chloroquine-resistant K1 strain of Plasmodium falciparum, with IC50 values of 0.78 and 0.52 μM, respectively. These compounds also demonstrated high selectivity indices, making them promising candidates for further development in antimalarial therapies (Ma et al., 2015). Zhu et al. (2017) identified two novel cassane diterpenoids, Caesalsappanin R and S, from C. sappan seeds. These compounds exhibited strong antiplasmodial activity, with Caesalsappanin R displaying the most potent effect, offering new possibilities for natural antimalarial agents (Zhu et al., 2017). Finally, Zuo et al. (2015) further explored the antibacterial properties of Protosappanins A and B from C. sappan heartwood. These compounds were found to be effective against MRSA and also demonstrated synergistic effects when combined with antibiotics such as amikacin and gentamicin, providing additional therapeutic options for combatting resistant bacterial infections (Zuo et al., 2015).

Settharaksa et al. (2019) demonstrated the significant impact of time and temperature in obtaining an optimal aqueous extract of C. sappan, with all extracts displaying potent antibacterial activity. The extracts were particularly effective against S. aureus, Staphylococcus epidermidis, and Propionibacterium acnes, making them promising candidates for antimicrobial applications (Settharaksa et al., 2019). Pattananandecha et al. (2022) further investigated the efficacy of ethanolic extracts from C. sappan heartwood, identifying the 70% ethanol extract as the most potent. After 24 h of treatment at 200 μg/mL, this extract was able to completely inhibit 100% of all pathogens tested, highlighting its remarkable antimicrobial potential (Pattananandecha et al., 2022). In another study, Techaoei (2022) tested ten Thai medicinal plant extracts against three fish pathogenic bacteria, with C. sappan emerging as one of the most promising. It exhibited substantial antimicrobial activity in time-kill kinetics assays, showing potential as an effective treatment against fish pathogens (Techaoei, 2022). Liu et al. (2023) identified Elizabethkingia miricola as the causative agent of infectious diseases in farmed American bullfrogs and evaluated the antibacterial properties of 60 traditional Chinese herbal extracts. Among these, C. sappan showed the lowest minimal inhibitory concentration (less than 0.2 mg/mL), indicating its high efficacy. When used in multicomponent herbal mixtures, the results were further enhanced, showcasing its potential in combating bacterial infections (Liu et al., 2023). Arjin et al. (2021) assessed the antiviral activity of ethanolic fractions from C. sappan against porcine reproductive and respiratory syndrome virus (PRRSV). The most effective fraction contained a combination of the coumarin compound Byakangelicin and flavonoids such as Brazilin, Naringenin, and Brazilein. These compounds were identified as key bioactive constituents responsible for the antiviral effects, positioning C. sappan as a promising natural treatment for PRRSV (Arjin et al., 2021). Jung et al. (2022) conducted a comprehensive screening of 16 medicinal plants for their antibacterial properties, with C. sappan among the most effective. The ethyl acetate fraction of C. sappan heartwood demonstrated strong antibacterial activity, exhibiting a favorable balance between minimum inhibitory and bactericidal concentrations while maintaining low cytotoxicity, underscoring its potential for safe and effective antimicrobial applications (Jung et al., 2022).

Cancer remains a significant global health issue, (Kudamba A et al., 2023). with projections estimating that by 2050, the number of new cancer cases will reach 35 million annually (Bray et al., 2024; Kaur et al., 2024). Although various treatment methods—such as chemotherapy, immunotherapy, radiotherapy, and surgical resection—have been employed, the effectiveness of these treatments is often hampered by drug resistance and side effects (Fakudze NT et al., 2023). This has led to increasing interest in alternative therapies, particularly those derived from medicinal plants, which contain bioactive compounds with antitumor, antiproliferative, and cancer-preventive properties (Memarzia A et al., 2023). In recent years, isolated compounds and extracts from C. sappan have gained attention for their potential efficacy against a wide range of cancers (Tables 6–8). Kwak et al. (2021) investigated the mechanisms of action of 3-Deoxysappanchalcone, an isolated compound from C. sappan, in esophageal cancer cells. The compound induced apoptosis and G2/M cell cycle arrest through the JNK/p38 MAPK signaling pathway, showing potential as an effective anticancer agent (Kwak et al., 2021). Similarly, Zhao et al. (2019) found that 3-Deoxysappanchalcone inhibited colon cancer cell proliferation by targeting the T-lymphokine-activated killer cell-originated protein kinase (TOPK) pathway. This treatment also increased the expression of cell cycle proteins such as cyclin B1 and induced apoptosis via cleaved PARP, caspase-3, and caspase-7 (Zhao et al., 2019). In another study, Wudtiwai et al. (2023) demonstrated that Brazilein, a compound from C. sappan, significantly inhibited the viability of triple-negative breast cancer cells by inducing apoptosis. The compound suppressed epithelial-mesenchymal transition (EMT), programmed death-ligand 1 (PD-L1), and the AKT, NF-κB, and GSK3β/β-catenin signaling pathways (Wudtiwai et al., 2023). Handayani et al. (2022) explored the synergistic effect of combining brazilein with the chemotherapeutic drug doxorubicin in breast cancer cell lines. The combination enhanced cytotoxic activity and inhibited cell migration by downregulating HER2, p120, and Rac1, while suppressing MMP2 and MMP9 proteins (Handayani et al., 2022). In a similar study, Handayani et al. (2017) investigated the combination of brazilin and brazilein with cisplatin in colon cancer cells. The combination potentiated the cytotoxic effects of cisplatin, inducing apoptosis and causing cell cycle arrest in the S phase (Handayani et al., 2017). Jeon et al. (2014) found that brazilin disrupts IKK signaling, interfering with the formation of the proximal IL-1 receptor signaling complex, thereby offering another promising approach to cancer treatment (Jeon et al., 2014). Additionally, Kim et al. reported that brazilin inhibits the barrier-to-autointegration factor (BAF) in lung and neuroblastoma cell lines (Kim S. H. et al., 2015). The synergistic effects of brazilin with doxorubicin were further highlighted by Jenie et al. (2018), who demonstrated that this combination promotes apoptosis through G2/M phase cell cycle arrest and Bcl-2 suppression, enhancing the cytotoxicity of doxorubicin (Jenie et al., 2018). Meanwhile, Kang et al. (2018) revealed that brazilin induces autophagy via the forkhead box class O (FOXO)3A pathway and disrupts calcium homeostasis in osteosarcoma cells (Kang et al., 2018). In breast cancer cells, Chatterjee et al. showed that brazilin downregulates DNMT1 expression by recruiting p53 to the DNMT1 promoter, restoring p21 expression (Chatterjee et al., 2022). Suyatmi et al. (2022) demonstrated that brazilin induces intrinsic apoptosis in lung cancer cells by increasing p53, caspase-9, and caspase-3 expression (Suyatmi et al., 2022). Additionally, in silico tests conducted by Correia Soeiro et al. (2022) indicated that brazilin interacts with BAF1, a protein implicated in carcinogenesis (Correia Soeiro et al., 2022). Wang et al. (2021) isolated three compounds—Caesaterosides A, B, and C—from the seeds of C. sappan. These compounds exerted cytotoxic effects on colon, uterine, and liver cancer cell lines (Wang et al., 2021). Su et al. (2024) identified three more compounds—Caesalpanin D, E, and F—among which Caesalpanin D activated autophagy and reactive oxygen species (ROS) generation in pancreatic cancer cells (Su et al., 2024). Jin et al. (2022) isolated eight compounds from C. sappan, with compound 8 showing the most promising antitumor activity (Jin et al., 2022). Zhang et al. (2014) demonstrated that ethyl acetate extracts from C. sappan inhibited liver cancer cell mitosis, while isolated compounds such as sappanchalcone, brazilin, and butein exhibited cytotoxic activities against various cancer cells (Zhang et al., 2014). The extract also showed antitumor efficacy in a mouse model bearing S180 tumor cells. Tran et al. (2015) isolated five compounds from C. sappan seeds, with Phanginin D emerging as the most potent antitumor agent, inducing apoptosis through caspase-3 activation in leukemia cell lines (Tran et al., 2015). Bao et al. (2016) identified five cassane diterpenoids, Phanginins R‒T (1–3) and Caesalsappanins M and N (4 and 5), with compound 1 inducing apoptosis and cell cycle arrest in ovarian cancer cells (Bao et al., 2016). Sappanchalcone, isolated by Seo et al. (2020), was shown to induce apoptosis by activating caspases-3, -7, -8, -9, and PARP in colon cancer cells (Seo et al., 2020). Naik Bukke et al. (2018) confirmed the cytotoxic activity of C. sappan heartwood and leaf extracts against breast and lung cancer cells in vitro. An in silico study further suggested that one of the primary components of brazilin inhibits the BCL-2 protein, enhancing its anticancer potential (Naik Bukke et al., 2018). Furthermore, an in silico study confirmed that one of the primary components of the brazilin extracts inhibited the BCL-2 protein.Widodo et al. used crude extracts from the C. sappan stem to investigate its anticancer mechanisms in lung cancer cell lines. The treatment induced apoptosis and negatively regulated mitochondrial proteins associated with tumor cell survival (Widodo et al., 2022). In a separate study, Haryanti et al. (2022) evaluated the combination of C. sappan and Ficus septica extracts with doxorubicin, finding that the combination enhanced doxorubicin’s cytotoxic properties and inhibited cell migration in breast cancer cells (Haryanti et al., 2022). Ma et al. (2020) demonstrated that ethyl acetate extracts from C. sappan heartwood induce mitochondrial apoptosis by increasing cytochrome C expression and activating ROS in acute myeloid leukemia cells (Ma et al., 2020). Hung and Dat (2014) showed that methanolic extracts from the core of C. sappan exhibited the most promising cytotoxic results, inducing apoptosis in colon cancer cells via caspase-3 activation (Hung and Dat, 2014). The methanolic extract exhibited the most promising results, inhibiting proliferation and inducing apoptosis via activation of caspase-3 in colon cancer cell. Finally, two plant mixtures containing C. sappan extract—Hua-Zheng-Hui-Sheng-Dan and MANOSROI III—demonstrated potent antitumor activity. Hua-Zheng-Hui-Sheng-Dan reduced tumor volume in mice (Cao et al., 2015), while MANOSROI III induced apoptosis in colon cancer cells and (Manosroi A et al., 2015a) exhibited significantly higher inhibitory effects on cell proliferation than cisplatin and doxorubicin (Manosroi A et al., 2015b). Inprasitet al. (2014) also found that Sa-Tri-Lhung-Klod, another mixture containing C. sappan extract, exerted cytotoxic activity in ovarian and colon cancer cells (Inprasit et al., 2014). Li et al. (2021) demonstrated the antitumor efficacy of petroleum ether extracts from C. sappan roots and leaves, with the leaf and stem extract (SY②) showing the best results in reducing liver tumor size in mice and downregulating PCNA and VEGF expression (Li et al., 2021).

Cancer therapies often focus on modulating cell death pathways, such as apoptosis, necrosis/necroptosis, and autophagy, which are crucial for the development of novel chemotherapeutic drugs (Hadian and Stockwell, 2023). Among these, apoptosis—commonly referred to as programmed cell death or “cell suicide”—is particularly significant (Merve Kulbay et al., 2021). Two major pathways mediate apoptosis: the intrinsic pathway, induced by cellular stress or regulated by B-cell lymphoma-2 (Bcl-2) family proteins, and the extrinsic pathway, initiated by death receptor ligands (Zhu M et al., 2023). Notably, C. sappan has demonstrated potent antitumor activity by activating the apoptosis pathway (Figure 4). Research shows that fractions of the crude extract and isolated compounds such as Phanginins R-T and Caesalsappanins M and N from C. sappan have the ability to increase the expression of Bcl-2 family proteins, which regulate mitochondrial outer membrane permeabilization, a key step in apoptosis. Apoptosis is facilitated by intracellular proteases called caspases, which are critical for initiating and executing the apoptotic process. These caspases are divided into initiator caspases (caspase 8, 9, and 10) and effector caspases (caspase 3, 6, and 7) (Kesavardhana and Kanneganti, 2020). Initiator caspases amplify apoptotic signals, subsequently activating effector caspases, which cleave cellular proteins to drive apoptosis (Kesavardhana and Kanneganti, 2020). Activation of caspase-9 indicates the intrinsic apoptosis pathway, while caspase-8 activation signifies the extrinsic pathway (Bock and Tait, 2020). Isolated compounds from C. sappan, including 3-Deoxysappanchalcone, Brazilin, and Sappanchalcone, have been shown to increase caspase-3 expression, with Sappanchalcone and Brazilin also promoting caspase-9 activation, underscoring their role in intrinsic apoptosis. Mitochondria play a central role in this process. Bcl-2 family proteins regulate mitochondrial outer membrane permeabilization, which triggers apoptosis via the release of cytochrome c (Chu et al., 2021). This mitochondrial mechanism was observed in the ethanolic extract of C. sappan, further emphasizing the plant’s pro-apoptotic properties. Additionally, autophagy is another important cell death pathway, although its relationship with cancer is complex. While autophagy can act as a survival mechanism for cancer cells, evidence also suggests it can suppress tumor growth under certain conditions (Li X and Ma, 2020). One crucial factor in autophagy is the phosphorylation of FOXO3, which induces autophagy (Ashrafizadeh et al., 2022). This mechanism has been demonstrated by the compounds Brasilin, Caesalpanin D, E, and F, isolated from C. sappan.

Furthermore, the isolated compounds and fractions from C. sappan have been shown to induce cell cycle arrest in tumor cells, a vital mechanism in controlling tumor progression. While mitosis is necessary for normal cell division, it becomes dysregulated in cancer cells, leading to uncontrolled proliferation (Huang et al., 2022). Caesalpinia sappan compounds target key regulatory proteins involved in mitosis, thereby inducing cell cycle arrest and promoting tumor cell death (Paier CRK et al., 2018).

Diabetes mellitus, a group of metabolic disorders characterized by persistent hyperglycemia, remains a significant global health challenge (Harreiter and Roden, 2023). Conventional treatments, such as oral hypoglycemic agents and insulin injections, offer temporary control of blood glucose levels but fall short in preventing long-term complications and often come with adverse side effects (Sun et al., 2021). This has led to growing interest in exploring alternative therapies, particularly those derived from medicinal plants, which offer benefits like enhanced safety, specific modes of action, and improved metabolic regulation. Research on compounds and extracts from C. sappan has shown potential in addressing diabetic symptoms and complications (Figure 5; Table 9). Studies conducted by Wediasari et al. (2020) demonstrated the potential of a combination therapy involving C. sappan and Andrographis paniculata, which yielded promising in vivo results. The combination significantly lowered blood glucose levels and increased pancreatic β-cell regeneration in diabetic rats, indicating its therapeutic potential for managing diabetes (Wediasari et al., 2020). Masaenah et al. (2021) further explored the combined effects of Andrographis paniculata, Syzygium cumini, and C. sappan extracts in diabetic rats. This treatment not only reduced fasting blood glucose levels but also moderately improved pancreatic β-cell function and maintained normal lipid profiles, without causing toxicity at the administered doses (Masaenah et al., 2021). These findings underscore the safety and efficacy of C. sappan as part of combination therapies for diabetes management. Wu et al. (2022) focused on Phanginin A, a compound isolated from C. sappan seeds, which demonstrated the ability to inhibit hepatic gluconeogenesis by increasing SIK1 phosphorylation. This mechanism significantly improved hyperglycemia in type 2 diabetic mice, suggesting that Phanginin A could be a valuable candidate for diabetes treatment (Wu et al., 2022). Wang et al. (2022) investigated the effects of Sappanone A, a compound derived from C. sappan heartwood, and found that it prevented diabetes-related complications such as renal inflammation and fibrosis. These effects were attributed to its inhibition of the NF-κB pathway, both in vitro and in vivo, highlighting its potential to alleviate diabetic complications at the molecular level (Wang et al., 2022). In an in silico study, Adnan et al. (2022) identified several bioactive compounds present in the crude extract of C. sappan wood, particularly Fisetin tetramethyl ether, which was found to activate the peroxisome proliferator-activated receptor (PPAR) signaling pathway. This pathway plays a crucial role in glucose homeostasis, further supporting the anti-diabetic potential of C. sappan (Adnan et al., 2022). The growing body of research on C. sappan extracts and isolated compounds provides compelling evidence of their potential as effective and safe alternatives for diabetes treatment. These findings pave the way for further studies to explore C. sappan’s therapeutic applications, particularly in combination with other medicinal plants.

Cardiovascular diseases, which encompass conditions such as heart attacks and strokes, primarily result from pathological changes in the heart or blood vessels (Nitsa A et al., 2018). These diseases are the leading cause of mortality worldwide, with atherosclerotic cardiovascular disease being the most prevalent contributor to overall deaths (Goldsborough E and Blaha, 2022). Despite significant advancements in treatment, cardiovascular diseases continue to pose a major global public health challenge, resulting in substantial social and economic burdens (Gao and Hou, 2023). Recent studies suggest that C. sappan extracts and its compounds could offer cardioprotective benefits, making it a promising avenue for cardiovascular health management (Figure 6; Table 10). Yan et al. (2015) demonstrated that Brazilin, a bioactive compound isolated from C. sappan, induces relaxation of aortic rings in rats, suggesting its potential to improve vascular function (Yan et al., 2015). This vasodilatory effect highlights Brazilin’s ability to enhance cardiovascular health by promoting healthy blood flow and reducing the strain on the cardiovascular system. Further research by Qi et al. (2021) revealed that Brazilin plays a protective role in preventing myocardial ischemia-reperfusion injury in rats. This cardioprotective effect is attributed to its activation of the Nrf2 pathway via protein kinase C (PKC), which underscores Brazilin’s potential to mitigate heart damage during ischemic events (Qi et al., 2021). Iqbal et al. (2023) explored Brazilin’s impact on proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. Elevated levels of PCSK9 are linked to an increased risk of cardiovascular disease. The study demonstrated that Brazilin effectively regulates PCSK9 levels, making it a promising candidate for cardiovascular disease prevention by helping to manage cholesterol levels and reduce atherosclerosis risk (Iqbal et al., 2023). Liu et al. (2022) investigated the effect of an ethyl acetate extract from C. sappan heartwood in an atherosclerosis model. The extract enhanced D-mannose production through the lysosomal pathway and improved lysosomal function in mice. This finding suggests that C. sappan may aid in combating atherosclerosis by promoting healthier cellular function and reducing plaque buildup (Liu et al., 2022). Lastly, Shi et al. (2020) focused on Sappanone A, another compound isolated from C. sappan, and its potential to prevent myocardial ischemia-reperfusion injury. The study found that Sappanone A modulates the Nrf2 pathway via PKC and PI3K, providing therapeutic benefits against myocardial injuries caused by ischemia (Shi et al., 2020). These studies highlight the potential of C. sappan and its compounds as promising natural interventions for cardiovascular disease. As a natural resource with diverse bioactive compounds, C. sappan may offer novel approaches for the prevention and treatment of cardiovascular conditions, contributing to improved heart health and overall well-being.

Several studies have highlighted the potential of C. sappan for the treatment of joint-related diseases, further showcasing the plant’s extensive range of health benefits (Table 11). Jung et al. (2015a) demonstrated that Brazilin, an active compound isolated from C. sappan, significantly reduced the arthritis index score and alleviated acute inflammatory paw edema in type-II collagen-induced arthritis (CIA) mice (Jung et al., 2015a). Notably, Brazilin prevented joint destruction and surface erosion, improved bone health, and significantly reduced the serum levels of key inflammatory cytokines such as TNF-α, IL-1β, and IL-6, thereby attenuating CIA in the model. Similarly, Jung et al. (2015b) also reported the effects of sappanchalcone, another compound from C. sappan, which was shown to decrease clinical arthritis severity and inflammatory paw edema in CIA mice. Treatment with sappanchalcone preserved bone mineral density and trabecular structure while significantly lowering the levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β. Weinmann et al. (2018) found that Brazilin reduced glycosaminoglycan (GAG) loss in cartilage explants stimulated with IL-1β and TNF-α, protecting cartilage from degradation. Analysis of the NF-κB pathway in chondrocytes revealed that NFKB1/p50 plays a key role in regulating Brazilin’s anti-inflammatory actions. Brazilin was able to suppress the IL-1β-induced upregulation of osteoarthritic (OA) markers and the activation of NFKB1/p50 in chondrocytes, suggesting a protective effect against OA progression. Kim et al. further explored the impact of Brazilin on bone health, showing that it inhibited RANKL-mediated osteoclast differentiation in RAW264.7 cells without causing cytotoxicity (Kim J. et al., 2015). Brazilin downregulated the expression of key osteoclast markers, including tartrate-resistant acid phosphatase (TRAP), NFATc1, matrix metalloproteinase-9 (MMP-9), and cathepsin K, while also reducing RANKL-induced expression of pro-inflammatory and osteoclastogenic factors such as iNOS, COX-2, TNF-α, and NF-κB p65. Additionally, in a lipopolysaccharide (LPS)-induced osteoporosis model, Brazilin was found to attenuate bone loss in vivo, further highlighting its bone-protective potential. Choo et al. (2017) focused on the role of Sappanone A, another compound from C. sappan, in preventing inflammation-induced bone loss. Sappanone A inhibited RANKL-induced osteoclastogenesis and bone resorption by targeting the AKT/glycogen synthase kinase-3β (GSK-3β) signaling pathway and NFATc1, suppressing downstream target genes such as CtsK, TRAP, MMP-9, DC-STAMP, and OSCAR. This study reinforced the compound’s potential as a therapeutic agent in preventing osteoclast-mediated bone diseases. Finally, Lee S. et al. (2015) reported that Brazilin enhanced autophagic flux in rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), as evidenced by increased autophagosome formation and elevated levels of lipidated LC3 (LC3-II), primarily mediated by increased ROS production (Lee S. et al., 2015). Additionally, Brazilin suppressed NF-κB activation and attenuated the inflammatory response under autophagy-inducing conditions in RA FLS, indicating its potential in managing rheumatoid arthritis by modulating autophagy and inflammation. These studies collectively highlight the multifaceted potential of C. sappan extracts and isolated compounds in treating joint-related diseases by modulating inflammatory and bone-degrading pathways, reinforcing its promise as a natural therapeutic agent for joint health.

The combination of C. sappan extracts and isolated compounds with existing cancer treatments presents a promising path for future research. The synergistic interactions observed in traditional formulations and individual compounds suggest the potential of C. sappan to enhance the effectiveness of conventional therapies, minimize adverse effects, and provide a more holistic approach to cancer management. Further studies, particularly clinical trials, are essential to fully elucidate the mechanisms and therapeutic benefits of these combination therapies. By emphasizing the plant’s dual role in antioxidant and anticancer mechanisms, and its broader therapeutic benefits spanning cancer, cardiovascular, and metabolic health, this review highlights the extensive potential of C. sappan in integrative cancer treatment.