Emodin is also known as 1,3,8-trihydroxy-6-methylanthraquinone, its chemical structural formula as shown in Figure 4, and contains the remaining 18 natural products. It is the active ingredient in the root and rhizome of Rhubarb. Studies have shown that emodin has a wide range of pharmacological effects, including antibacterial, immunomodulation, anti-inflammatory, anti-tumor and enhanced cancer chemotherapy (Semwal et al., 2021; Zhang et al., 2022; Wang et al., 2023). It has been suggested that rhodopsin may impede the migration and invasion of melanoma B16F10 and A375 cells by inhibiting the Wnt/β-Catenin signaling pathway (Liu et al., 2021). Furthermore, rhodopsin also inhibits the growth of cancer cells by downregulating CD155 in melanoma B16F10 cells (Fang et al., 2019). Therefore, rhodopsin may be a potential drug for treating highly metastatic melanoma.

Aloe-emodin is an anthraquinone extract from the vine with the chemical formula C15H10O5 (Bhat and Kudva, 2011). Aloe-emodin has numerous pharmacological effects, including anti-inflammatory, immunomodulatory, and wound healing (Dong et al., 2020; Luo et al., 2024). New evidence showed that aloe-emodin exhibited anti-cancer ability in various cancers by inhibiting cell proliferation, migration, and invasion (Sanders et al., 2017). It was experimentally demonstrated that the proliferation, migration, and invasion ability of A375 and SK-MEL-28 melanoma cells treated with aloe-emodin were significantly inhibited, and the growth of A375 and SK-MEL-28 melanoma cells was affected by the inactivation of the Wnt/β-catenin signaling pathway. Furthermore, aloe-emodin also significantly inhibited the growth of A375 and SK-MEL-28 cells in the mouse model of transplantation tumors (Du et al., 2021). Therefore, aloe-emodin could be a potential treatment for melanoma.

TAP7f have anti-proliferative activity against different tumor cell lines (Bellizzi et al., 2022). Its anti-proliferation activity against tumor cells is 30 times higher than that against normal cells. Research has demonstrated that TAP7f exerts antitumor effects by inducing cell cycle arrest and activating death receptors and mitochondria-dependent apoptotic pathways in melanoma B16-F0 cells. Moreover, the melanoma tumor growth in the mouse model treated with TAP7f was reduced by 70% (Blank et al., 2018). New research has recently revealed that TAP7f may inhibit melanoma cell proliferation, migration, and invasion by blocking the Wnt/β-catenin pathway, reducing β-catenin nuclear translocation, and decreasing β-catenin and specific downstream targets (Barrionuevo et al., 2020).

CoQ0 also known as 2,3 dimethoxy-5-methyl-1,4 benzoquinone, is a common ubiquinone compound with redox activity widely found in biological mitochondria. CoQ0 has been demonstrated to have proliferative inhibitory effects on various cancer cell lines (Chung et al., 2014; Wang et al., 2017). In vitro experiments have shown that CoQ0 inhibits the proliferation of melanoma B16 cells by suppressing β-catenin-induced transcriptional activation and by nuclear translocation of the β-catenin proteasome. In B16F10 xenograft mice, the expression of β-catenin, Cyclin D1, Survivin, and MMP-9 was significantly reduced in the CoQ0-treated animal model (Hseu et al., 2016). These data demonstrate that CoQ0 inhibits cell growth and apoptosis and prevents metastasis by suppressing melanoma cells’ Wnt/β-linked protein signaling pathway.

Resveratrol is a dietary product found in grapes, vegetables, and berries. Resveratrol has been reported to affect each stage of carcinogenesis. Many studies demonstrate that resveratrol can be an ideal anti-cancer molecule because it has a cytotoxic effect on cancer cells (Jang et al., 2022). Studies have shown that resveratrol may induce ROS production and ER stress, thereby hindering the antioxidant effect of resveratrol and enhancing apoptosis of melanoma A375SM cells (Heo et al., 2018), revealing the potential use of resveratrol in the treatment of melanoma. A study has found that resveratrol downregulates the protein level of anti apoptotic protein Bcl-2 and activates Bax by promoting the degradation of Bcl-2 and the release of cytochrome c. In addition, they found that PKM2 plays a crucial role in triggering cell apoptosis. Summarizing that resveratrol in melanoma cells and downregulating the Erk/PKM2/BCl-2 axis seems to be a new method for preventing or treating melanoma (Zhao et al., 2018).

δ-TT is found in a wide variety of natural products. Due to its powerful neuroprotective, anti-inflammatory, antioxidant, and cholesterol-lowering potential (Ahsan et al., 2014; Peh et al., 2016). It works in various chronic diseases, and δ-TT shows antitumor activity as well (Wang et al., 2022). It has been demonstrated that δ-TT triggers cell death and activates ER stress-related pathways such as PERK/p-eIF2α/ATF4/CHOP and IRE1α to induce apoptosis in melanoma cells and that δ-TT significantly inhibits tumor growth rate in A375 melanoma animal model (Montagnani et al., 2016). These studies suggest that δ-TT may also be a potential drug for the treatment of melanoma.

Cudraflavone C is a natural flavonoid compound with anti proliferative activity, which was initially found to inhibit melanin production (Zheng et al., 2012; Chan et al., 2021). Tumor specific apoptosis of rectal cancer cells can be induced by targeting the PI3K/AKT pathway (Soo et al., 2018). Research proves that cudraflavone C induces apoptosis in A375.S2 melanoma cells by increasing the production of mitochondrial ROS, activating p38, ERK and JNK, and increasing the expression of apoptotic proteins (Lee et al., 2017). Thus, cudraflavone C may be considered a potential therapeutic agent for treating malignant melanoma.

11-Dehydrosinulariolide is a cembranolide analog, with a variety of biological activities (Chen et al., 2016). It has also been shown that 11-dehydrosinulariolide induces apoptosis in human melanoma cells by up-regulating PERK/eIF2α/ATF4/CHOP and ATF6/CHOP coupled with elevated ER stress chaperones GRP78, GRP94, calcium-linked protein, calreticulin, and PDI, which impede cystein-dependent mitochondrial function and ER stress pathway in human melanoma cells A2058 (Su et al., 2012). The present findings suggest that 11-dehydrosinulariolide is an effective compound against powerful melanoma cells in vitro, facilitating the drug development of anti-melanoma drugs.

Shikonin is a natural product isolated from comfrey, a member of the comfrey family, and has long been used in China to treat inflammation, burns, ulcers, infections, and cancer (Sun et al., 2022). Experiments have shown that increased phospho-ERK1/2, phospho-JNK, and phospho-p38 were observed in phycocyanin-treated cells, and total-ERK1/2, total-JNK, and total-p38 tended to decrease in phycocyanin-treated cells. Identifying apoptosis in A375SM melanoma cells induced by comfrey treatment through MAPK pathway. In a mouse animal model, the tumor volume was reduced by Shikonin administration. P38, an essential protein in the MAPK pathway, was significantly increased (Liu et al., 2019). The above results demonstrate that the apoptosis induction of paclitaxel in A375SM melanoma cells seems to be mediated by the expression of ERK and JNK proteins in the MAPK pathway, especially the expression of p38 (Lee et al., 2021).

L. barbarum is a traditional Asian food and medicine rich in zeaxanthin. Many studies have shown that L. barbarum extract has immunomodulatory effects and anti-tumor activity (Ceccarini et al., 2016; Wawruszak et al., 2016). L. barbarum extract containing zeaxanthin has been shown to inhibit the proliferation of human melanoma A375 cells, induce the expression of MAPK factors ERK1/2, JNK, and p38 in A375 skin cells, upregulate total NF-kB, thereby inducing apoptosis and reducing tumor cell growth. Therefore, L. barbarum extract may be used as an adjuvant for standard antitumor chemotherapy (Cenariu et al., 2021).

PLB is a naphthoquinone derivative derived mainly from plants that exhibit anti-cancer potential in different cancers (Yin et al., 2020; Zhang et al., 2020). Plumbagin was shown to downregulate MAPK-related genes, including Map3k3, MAPK14, Braf, c-Myc, and MAPK1, and induce enhanced gene expression of Igfbp5 and Pten, thus promoting further activation of the MAPK pathway, and thus acting as an anti-invasive and anti-metastatic agent in melanoma B16F10 cells (Alem et al., 2020). Meanwhile, PLB can trigger cell-specific cytotoxic effects and metabolic responses in melanoma A375 cells (Zhang et al., 2021). Combining Celecoxib and Plumbagin reduces the proliferation of melanoma cells and inhibits COX-2 and STAT3-mediated tumor vascular development, thereby inducing apoptosis in human fibroblast FF2441 cells (Gowda et al., 2017). Hence, it is necessary to investigate PLB as an antitumor agent and further develop its potential clinical applications.

Bee Venom (BV) is a natural toxin produced by honey bees (Apis mellifera) and has been widely used as a traditional medicine for many diseases (Sadek et al., 2024). Melittin is the main bioactive component of BV. Moreover, in the current study, melittin has been shown to act against melanoma A375 cells by downregulating PI3K/AKT/mTOR and MAPK signaling pathways. Moreover, the growth, migration, and invasion of melanoma B16F10, A375SM, and SK-MEL-28 cells treated with different melittin concentrations were inhibited (Lim et al., 2019). Ultrasmall lipid nanoparticles driven by mixed melittin proteolytic peptides inhibit tumor cell growth in a mouse melanoma model, with no side effects observed (Huang et al., 2013). The current findings suggest that melittin could be used as a potential targeting agent in melanoma treatment.

Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a dietary flavonoid found in various fruits and vegetables, including strawberries, grapes, apples, onions, and cucumbers (Khan et al., 2018). In many biological activities, including neuroprotective, anti-arthritic, and anti-allergic activities (Ahmad et al., 2017; Zheng et al., 2017). Fisetin was shown to inhibit phosphorylation of MEK1/2 and ERK1/2 in the MAPK signaling pathway activation pathway and inhibit NFκB in signaling to reduce melanoma A375 cell invasion and metastasis. Fisetin reduced the invasion of melanoma cells into the dermis in 3D skin consisting of A375 cells mixed with average human keratin-forming cells embedded in a collagen-constricted fibroblast matrix (Pal et al., 2014). In 3-D melanoma constructs, fisetin inhibits the growth of human melanoma A375 cells by directly binding to p70S6K and mTOR (Syed et al., 2014). The above experimental results demonstrate that fexofenadine can be developed as a potential anti-melanoma drug.

PPI is a bioactive component derived from Paris polyphylla with a wide range of biological and pharmacological activities (Yang et al., 2024; Zhang et al., 2024). It was demonstrated that the expression of p-PI3K, p-Akt, and p-mTOR was significantly reduced in A375 cells after PPI treatment, and inhibited melanoma cell proliferation and enhanced melanoma cell apoptosis by suppressing PI3K/Akt/mTOR signaling pathway, which blocked melanoma cells at G0/G1 stage, thus reducing melanoma progression. In addition, the weight and size of melanoma mice treated with PPI was significantly reduced, and apoptosis of melanoma cells was significantly enhanced (Long and Pi, 2020). Therefore, PPI may be a promising, targeted drug for melanoma treatment.

Scutellarin (4′,5,6-hydroxyl-flavone-7-glucuronide) is a flavonoid derived from Calendula officinalis with a variety of functions including antioxidant, anti-inflammatory, cardioprotective, and vasodilator (Wang and Ma, 2018). Scutellarin promotes A375 cell apoptosis by upregulating bax and cleaved caspase-3 levels, downregulating bcl-2 levels, Inhibit the growth of A375 cells in G0/G1 phase, Enhance cellular autophagy by regulating the levels of Beclin 1, LC3II, and p62. And block the melanoma cell cycle by inhibiting the PI3K/Akt/mTOR signaling pathwa (Li et al., 2019). It has also been demonstrated that lanosterol inhibits the proliferation of human melanoma cells RPMI7951 melanoma cells by targeting TOPK. In addition, in vivo experiments demonstrated that SCU inhibited the growth of RPMI7951 cell xenografts and reduced the phosphorylation levels of ERK 1/2 and histone H3 in vivo (Mu et al., 2021). It suggests that scutellarin may be a potential compound for treating malignant melanoma.

Bornyl cis-4-hydroxycinnamate, an active compound isolated from Piper betle stem, could inhibit cell viability, migration, and invasion of A2058 and A375 melanoma cells in a dose-dependent manner. The expression of FAK/PI3K/Akt/mTOR signaling-related proteins, including Akt, p-Akt, PI3K, p-PI3K, mTOR, p-mTOR, and FAK, was reduced in cis-4-hydroxycinnamate treated melanoma cells, which inhibited the metastasis of human melanoma cells through the FAK/PI3K/Akt/mTOR signaling pathway (Yang et al., 2018a). Additionally, cis-4- hydroxycinnamate has been shown to mediate apoptosis in melanoma cells by activating the cystathionine cascade, inducing mitochondrial dysfunction, and causing endoplasmic reticulum stress-related stress mechanisms (Yang et al., 2018b). The above results demonstrate that bornyl cis-4-hydroxycinnamate can potentially be a chemotherapeutic agent for human melanoma development.

Sinomenine (7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methylmorphinane-6-one; SIN) is the active compound of the Chinese herb Cyanidin. SIN has an antitumor effect (Gao et al., 2019), including lung cancer and breast cancer (Song et al., 2015; Jiang et al., 2016). Recent studies have shown that SIN inhibits proliferation and promotes apoptosis in melanoma B16F10 cells via PI3K/Akt/mTOR-dependent autophagic pathway. In a melanoma xenograft mouse model, tumor volume and weight were significantly reduced after SIN treatment, and the expression levels of Ki67 and PCNA were significantly reduced (Sun et al., 2018). It suggests that SIN can reduce the tumor growth of melanoma in vivo. However, SIN also has some disadvantages, for example, poor gastrointestinal response, short biological half-life, and unstable physicochemical properties (Zhang et al., 2018). Therefore, the role of SIN in the treatment of melanoma deserves further investigation.

TanIIA, a compound isolated from Salvia miltiorrhiza, has various biological activities, including apoptosis and autophagy, anti-inflammation, oxidation, anti-thrombosis, and anti-proliferation of vascular smooth muscle cells (Luo et al., 2015; Naz et al., 2020). It was shown that the phosphorylation levels of PI3K, P-AKT, P-mTOR, and P-p7036k1 were reduced in melanoma A375, MV3, and M14 cells treated with TanIIA, which inhibited the proliferation and invasion, and migration ability of melanoma cells, and promoted the autophagosome production of A375, In addition, TanIIA inhibits the development of A375 melanoma-induced tumor weight and volume in mice (Li et al., 2017). Research has found that TanIIA photosensitization has significant toxicity to choroidal melanoma cells and can effectively induce cell apoptosis and necrosis. Increase intracellular ROS levels, decrease mitochondrial membrane potential, and cause cell arrest in G2/M phase (Juan et al., 2021). In a recent report, the first study to link Tan IIA induced ferroptosis with the STAT1/PTGS2 axis in melanoma was found. Tan IIA regulates the key marker of ferroptosis, PTGS2, and knocking down PTGS2 weakens Tan IIA induced ferroptosis in melanoma cells. In addition, they found that Tan IIA stimulated the downregulation of signal transduction and transcription factor STAT1, leading to the downregulation of PTGS2 and inhibiting ferroptosis in melanoma (Chen et al., 2025).

UA3-(β-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid compound commonly found in fruits, foods, and medicinal plants (Castro et al., 2015; Huang et al., 2015; Yin et al., 2018). Recent experiments have shown that ursolic acid activates the proteolytic processing of caspase-3 in isolated human melanoma cells and induces apoptotic cell death (Mahmoudi et al., 2015; Alvarado et al., 2018). Nanoemulsion of ursolic acid isolated from egg flowers enhances melanoma cells’ antioxidant and cytotoxic activity. When UA and chloroquine were synergistically applied to B16F10 mouse melanoma and A375 human melanoma cells, cell viability was strongly reduced (Junco et al., 2015). The above results suggest that ursolic acid could be a new potential tool for further research as an anti-cancer agent.

Capsaicin is a component of chili peppers, the active ingredient in chili peppers. Capsicum is widely used as a pungent spice in food. Previous studies have demonstrated that capsaicin has anti-inflammatory, analgesic, anesthetic, and detoxifying effects (Bernstein et al., 2011; Patel et al., 2014; Fattori et al., 2016). Capsaicin was shown to affect cancer cell viability negatively and induce apoptosis in human melanoma A375 and C8161 cells by activating cleaved caspase-3 and PARP (Chu et al., 2019). There is also evidence that capsaicin inhibits the growth of SK-MEL-28 melanoma cells and increases apoptosis by inhibiting plasma membrane NADH oxidase activity (Morré et al., 1996). Capsaicin also inhibits the migration of B16-F10 melanoma cells by suppressing the PI3K/AKT/Rac-1 pathway (Shin et al., 2008). Therefore, capsaicin administration can be an effective method for the treatment of malignant melanoma.

Toad venom is a traditional natural medicine that has been used for centuries in China, and a growing body of research suggests that toad venom is a source of lead compounds for the development of potential cancer therapeutics (Li et al., 2021). Na⁺/K⁺ATPase is overexpressed in a variety of cancer types, including metastatic melanoma. Recent studies have shown that toad venom’s active ingredient, toadienolactone, acts on the Na⁺/K⁺-ATPase pump to exert anti-proliferative effects on melanoma cells (Soumoy et al., 2020). Bufalin, another active ingredient, can act through extrinsic and mitochondrial-mediated signaling pathways to trigger apoptosis (Hsiao et al., 2012). Bufalin can also potentially stimulate tyrosinase activity to promote melanin synthesis (Zhang et al., 1992). It may lead to the production of toxic melanin precursors, which inhibit melanoma growth.

Silymarin is the main bioactive component of silybum marianum and has long been used for the prevention of allergies and liver damag (Gillessen and Schmidt, 2020). Several studies have demonstrated the chemopreventive or chemotherapeutic effects of silymarin on various cancers (Dagne et al., 2011; Ramasamy et al., 2011). It has been shown that silymarin induces cell cycle arrest and inhibits the growth of human melanoma SK-MEL-5 and SK-MEL-28 cells in the G1 phase by blocking MEK1/2-RSK2 signaling, leading to a decrease in the activation of various transcriptional regulators of proliferation genes in melanoma, such as nuclear factor-kappaB, activator protein-1, and signal transduction and transcriptional activator 3. Silymarin also attenuates the growth of melanoma xenografts in nude mice (Lee et al., 2013). Furthermore, the combination of cold atmospheric plasma and silymarin nanoemulsion inhibited the HGF/c-MET signaling pathway to promote apoptosis in G-361 human melanoma cells and reduce tumor growth in a tumor xenograft nude mouse model (Adhikari et al., 2019), as shown in Table 1.