Triptolide (TP), an abietane-type diterpenoid isolated from Tripterygium wilfordii Hook. F, possesses potent antitumor, immunosuppressive, and anti-inflammatory properties[4]. TP exerts its anticancer effect primarily through inducing apoptosis[5,6]. TP can promote apoptosis in Eca-9706 cells by stimulating damage due to oxidative stress and inhibiting stress reduction reactions (Table 1 and Figure 3).

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Figure 3 The structural formulae of natural products targeting oxidative stress.

Deguelin, the most common rotenone compound in plants apart from rotenone itself, is found in the roots of Tephrosia toxicaria, Derris trifoliata, Piper cubeba, and the leaves of Tephrosia vogelii. Which has pharmacological effects such as antiviral and anti-tumor effects. In recent years, deguelin has been discovered to possess strong anticancer activity[7]. Deguelin induces cell apoptosis by blocking anti-apoptotic pathways such as PI3K-Akt, IKK-IκBα-NF-κB, and AMPK-mTOR-survivin. Some results demonstrated that increasing deguelin concentration significantly inhibits the proliferation of ESC EC-109 cells and plays a crucial role in inducing apoptosis.

Doxofylline is a novel methylxanthine derivative known for inhibiting phosphodiesterase and exerting effects on airway expansion, anti-bronchospasm, and improved ventilation function[8]. Doxofylline is involved in the oxidative stress response of cancer cells and exhibits immune regulation, anticancer, and anti-inflammatory properties[9]. Another study revealed that doxofylline reduces inflammatory response and oxidative stress in patients undergoing radical resection of ESC.

Naringin (NR), also known as NR, citrin, and isohesperidin, is a dihydroflavonoid mainly found in the peel and pulp of grapefruit, tangerine, and orange in the Rutaceae family[10]. NR is a dihydroflavonoid. Because no conjugation exists between ring A and ring B, NR has a strong ultraviolet absorption peak at 282 nm, which makes it display a variety of biological activities and pharmacological effects, including anti-inflammatory, anticancer, and immunomodulatory effects. Tajaldini et al[11] showed that doxorubicin combined with NR resulted in reduced systemic toxicity and decreased fractional cycling of oxidative stress.

Astaxanthin (AST), a carotenoid present in various organisms such as red yeast, red algae, chlorella, shrimp, and crab shells. In addition to its carotenoid functions that alleviate visual fatigue and prevent light damage, it also has strong pharmacological properties such as antioxidant, anti-tumor, and immune enhancement. Cui et al[12] revealed that AST inhibits NF-κB and COX expression, improves antioxidant capacity and anti-inflammatory ability, and significantly inhibits the occurrence of ESC. Another study by Cui et al[12] demonstrated that AST inhibits oxidative stress by increasing the levels of SOD and total antioxidant capacity (TAOC) in serum while inhibiting the levels of MDA and increasing the protein expression of PPARγ, Bax/Bcl-2, and caspase-3 in esophageal tissues, thus providing protective effects against ESC.

Gypenosides (GP), the effective components of Pentaphyllum japonica, a traditional Chinese medicine, exhibit significant pharmacological activities such as cancer inhibition, anti-inflammatory, and blood pressure lowering[13]. GP plays a role in cellular self-repair, promotes cancer cell recovery, prevents tumor recurrence and metastasis, and inhibits the proliferation of nearly all cancer cells[14]. Yan et al[15] demonstrated that GP inhibits the proliferation and migration of ESC Eca-109 cells in a dose- and time-dependent manner. It increases intracellular ROS levels, reduces mitochondrial membrane potential, and induces apoptotic morphologies such as cell shrinkage and chromatin condensation, indicating that oxidative stress and mitochondria-dependent apoptosis are involved in GP-induced loss of cell viability in ESC Eca-109 cells.

Galangin (3,5,7-trihydroxyflavone), a natural flavonol compound, is the main active ingredient in the rhizoma of galangal, a traditional Chinese medicine[16]. It possesses anti-inflammatory, free radical scavenging, and anti-cancer effects[17]. Available data suggest that galangin, as a free radical scavenger, exhibits various pharmacological activities and confers resistance against the growth of different tumors. Ren et al[18] found that galangal plays a crucial role in inhibiting the proliferation of ESC cells by inhibiting the activity of cyclins and cyclin-dependent kinases. Additionally, galangin enhances the expression of P53 and its family members P21 and P27, further inhibiting the growth of cancer cells[19]. Moreover, galangin exerts its influence by inhibiting the PI3K/JAK2/STAT3 signaling pathway, which becomes activated in the presence of ROS. Galangin reduces ROS levels and inhibits the activity of this signaling pathway, thereby effectively inhibiting the growth and survival of ESC cells[20].

Berberine (BBR) is a quaternary ammonium bioactive base isolated from the traditional Chinese medicine Coptidis rhizoma, known for its various pharmacological effects such as anti-inflammatory and antibacterial effects and participation in cellular oxidative stress response[21,22]. It inhibits cancer cell proliferation and induces cancer cell apoptosis[23]. Moreover, BBR has shown potential in inhibiting cell proliferation, invasion, and metastasis in different cancers through cell cycle arrest, senescence, apoptosis, and autophagy of tumor cells, making it a promising anticancer drug. In the study by Jiang et al[24], the effects of BBR on ESCC line KYSE-70 and esophageal adenocarcinoma cell line SKGT4 were evaluated. The results showed that BBR inhibited EC cell growth by promoting cell cycle arrest and apoptosis in G2/M phase.

Echinatin (Ech), a compound extracted from licorice, a classic Chinese herbal medicine, demonstrated multiple biological activities, especially in terms of antitumor and anti-angiogenesis activities, garnering extensive attention in recent years[25]. The results of Kwak et al[26] showed that Ech induced apoptosis in human ESC cells by increasing ROS levels, endoplasmic reticulum (ER) stress, and p38 MAPK/JNK activation.

Thapsigargin (TG), derived from Thapsia garganica L., a plant known for its potential anticancer properties, has demonstrated promising activity against various types of tumor cells[27]. It exerts its effects by inducing ER stress and apoptosis, thereby inhibiting cancer growth. CHOP, a key transcription factor, plays an important role during ER stress. In this context, forced expression of CHOP can upregulate the expression of death receptor 5 (DR5) and promote oxidative stress and cell death[28]. TG effectively activates the ER stress response, while an increased protein folding load in the ER leads to ROS accumulation[28]. Ma et al[29] revealed that TG enhances the sensitivity of human ESC cells to TRAIL-induced apoptosis by depleting the cellular TAOC and increasing ROS levels in human ESCC cells.

Ziyuglycoside II (ZYG II), derived from Sanguisorba officinalis L., is a triterpene saponin with good anti-inflammatory and anticancer properties[30]. It exerts its pharmacological effects mainly by inducing ROS production and apoptosis[31]. Zhong et al[32] demonstrated that ZYG II significantly induces apoptosis of digestive tract tumor cells by regulating cell cycle progression, mediating oxidative stress, and blocking the epidermal growth factor receptor (EGFR) signaling pathway, thereby promoting the anticancer effect of 5-fluorouracil (5-FU).

α-Hederin belongs to the monosaccharide chain pentacyclic triterpene saponins, and it is found in various plants such as Hedera helix L., Fructus Akebiae, and Nigella sativa L[33]. It has been shown to possess various pharmacological effects, including antitumor, anti-inflammatory, antispasmodic, and anti-leishmaniasis properties[34]. In the study by Wang et al[35], the antitumor effect of α-hederin was evaluated in vivo using the human ESC cell line Eca-109. The results demonstrated that α-hederin significantly inhibited ESCC cell proliferation, induced cell apoptosis, and arrested the cell cycle at the G1 phase. α-Hederin inhibits ESCC cell proliferation and induces apoptosis by dispersing mitochondrial membrane potential (MMP) and simultaneously generating ROS and activating the mitochondrial pathway.

Lycopene, a type of carotene found in plant foods, it has pharmacological effects such as enhancing the body's oxidative stress capacity, anti-inflammatory effects, antioxidant effects, and enhancing immunityis abundant. It can be found in ripe red plant fruits, particularly in tomatoes, carrots, and guavas[36]. Unlike β-carotene, lycopene lacks the β-angelone ring structure, preventing its conversion into vitamin A in the body[37,38]. Although it lacks the physiological activity of vitamin A, lycopene possesses a potent antioxidant function[38,39]. Cui, Lingling et al revealed that an appropriate dose of lycopene effectively reduces the incidence of ESC induced by JV-nitrosomethylbenzylamine (NMBzA) in F344 rats. Lycopene significantly reduces the expression of PPARγ, NF-κB, COX-2, and caspase-3 proteins involved in oxidative stress, exhibiting anti-inflammatory and pro-apoptotic effects[40].

Daphnetin (DAP) is an active ingredient extracted from Daphne Koreana Nakai, also known as Zushimazin[41]. It is the first new drug in China and is chemically named 7,8-dihydroxycoumarin. Its pharmacological effects primarily involve triggering ROS-induced apoptosis and inhibiting the production of tumor necrosis factor-α, interleukin-1β, ROS, and MDA[42-44]. Daphnetin demonstrates remarkable anti-inflammatory, antioxidant, and anticancer abilities. In vivo experiments have shown that DAP administration as a standalone treatment reduces tumor volume and slightly increases body weight in experimental mice. Furthermore, co-administration of Dox and DAP not only reduces tumor volume but also preserves body weight, indicating that DAP exerts a protective effect against oxidative stress in vivo[45].

Vitamin E is an essential fat-soluble vitamin in the human body[46]. It serves as a crucial nonenzymatic, chain-breaking antioxidant distributed in the cell membrane of aerobic organisms. Its pharmacological effects mainly include antioxidant, anticancer, vascular protection, and regulation of hormone levels in the body. Vitamin E effectively prevents and reduces nonenzymatic oxidative damage to DNA and lipids caused by free radicals or ROS and plays a protective role in biofilm[47,48]. A study by Eskelson et al demonstrated that ethanol increased the incidence of NMBzA-induced esophageal tumors by 174%, while a vitamin E-supplemented diet reduced the incidence of ethanol-induced esophageal tumors by 32%. Mice supplemented with vitamin E also showed a reduced number of esophageal tumors, suggesting that vitamin E exerts a protective effect by interrupting the chain reaction of free radicals[49].

Alantolactone is a perennial herb belonging to the genus Inula in the Asteraceae family. The root of Inula helenium L. contains a large amount of sesquiterpene lactones, mainly including alantolactone and isoalantolactone (IAL)[50]. IAL possesses various biological activities such as anti-inflammatory, antioxidant, antitumor, and neuroprotective effects. It exhibits cytotoxic effects on a variety of cancer cells but has no significant toxicity on normal cells[51]. Lu et al[52] demonstrated that IAL induces apoptosis in human ESC cells by activating caspase-3, -7, and -10 and upregulating DR5 (an extrinsic pathway). This process involves upregulating DR5 and increasing ROS.

Morphine is an NP extracted from the milk of the poppy plant (Papaver somniferum)[53]. This plant is a perennial herb mainly found in the Mediterranean region and some parts of Asia. It is widely used in medicine to alleviate severe pain due to its powerful analgesic, sedative, and cough relieving pharmacological effects, especially after surgery or during cancer treatment or severe trauma[54]. Morphine also plays an important role in ESC treatment[55,56]. Zhang et al[57] demonstrated that morphine activates the AMP-activated protein kinase (AMPK) pathway, induces epithelial-mesenchymal transition, and increases oxidative stress in ESC cells by upregulating Snail and Slug expression levels.

Quercetin is a natural flavonoid with a wide range of biological activities, found abundantly in flowers, leaves, and fruits of plants. Its effects include antioxidant, anti-allergic, anti-infective, and antiviral properties[58,59]. Recent studies have also revealed its inhibitory effects on various cancers including ESC and thyroid cancer. Zheng et al[60] reported that quercetin is considered a potential chemopreventive agent because of its involvement in inhibiting oxidative stress, proliferation, and metastasis throughout the cancer process.

Alpinumisoflavone (AIF) is a flavonoid compound isolated from the stem bark of the tung tree. AIF exhibits anticancer properties against various cancer cells including colorectal, esophageal, renal, and hepatocellular carcinomas[61]. AIF possesses multiple therapeutic effects, such as anti-osteoporotic, antioxidant, anti-inflammatory, antibacterial, anticancer, and neuroprotective properties[62]. According to Zhang, Bin et al, AIF significantly enhances the radiosensitivity of ESCC cells in vitro and in vivo by targeting the pathways of DNA damage, apoptosis, and cell cycle arrest induced by radiation[63]. Specifically, AIF inhibits the expression of nuclear factor Nrf2 and the NrF2-regulated antioxidant molecules NQO-1 and HO-1, thereby exacerbating the radiation-induced ROS production in ESCC cells.

Raspberries, also known as Rubus idaeus L., are available in various varieties. Black raspberries (BRBs) are well known for their anticancer, antihypertensive, and antioxidant abilities[64]. BRB are rich in anthocyanins, which are excellent natural antioxidants with the ability to scavenge ROS such as superoxide anion, oxygen (O₂), peroxide, and hydrogen peroxide (H₂O₂) free radicals, exhibiting stronger lipid peroxidation than other antioxidants. BRB counteracts oxidative stress and suppresses NFκB/MAPK pathways, contributing to the chemopreventive action against ESC in rats[65].

Moringa oleifera leaf extract (MOE) is a natural plant nutrient extracted from Moringa oleifera leaves. It contains a large amount of antioxidants and minerals and possesses anti-inflammatory, hypoglycemic, and metabolic effects. Compounds present in MOE can inhibit the growth and spread of cancer cells[66-68]. Tiloke et al[69] revealed that MOE administration significantly enhances the expression of Smac/DIABLO protein and cleavage of PARP-1, leading to a noticeable increase in the 24-kDa fragment. This extract exerts potent anti-proliferative effects on SNO EC cells through increased lipid peroxidation, DNA fragmentation, and induction of apoptotic cell death.

This review highlights the beneficial effects of NPs in preventing ESC and treating cancer by targeting the antioxidant stress pathway. ESC prevention and treatment have significant clinical and societal importance, but current drug options are limited. Chemopreventive medications such as fluorouracil[70], cisplatin[71], and paclitaxel[72] have shown efficacy in preventing ESC, but prolonged use may lead to undesirable effects such as gastrointestinal reactions, mucosal injury, and renal toxicity. By contrast, NPs offer multifaceted effects in ESC prevention and treatment, including reducing DNA damage, protecting normal tissues, inhibiting cancer cell proliferation, and even reversing carcinogenesis.

The complex pathogenesis of ESC requires a multi-target and multi-pathway approach for treatment. NPs possess various activities such as antioxidant, anti-inflammatory, and modulation of signaling pathways[73]. These actions positively influence the development of ESC through various signaling pathways. NPs can directly or indirectly affect ESC by modulating pathways like PI3K/Akt, Wnt/β-catenin, NF-κB, and ROS/MAPK through their effect on oxidative stress. These findings demonstrate that NPs possess the ability to modulate ESC development through a multi-targeted and multi-pathway approach[74]. These results establish a foundation for future investigations in cellular and animal studies, allowing for further exploration of the potential of NPs in regulating ESC development.

Doxofylline has shown potential benefits as an effective adjunctive treatment for ESC in clinical trials. However, these treatment methods are still in the early stages and have limitations in their current application. The transformation of NPs into pharmaceuticals remains a significant challenge owing to factors such as chemical instability, rapid metabolism, and potential side effects[75]. A major limitation of NPs is their low oral bioavailability, which restricts the clinical use of certain NPs containing beneficial bioactive ingredients including Ech and lycopene.

At present, NPs are not widely accepted by the clinical and mainstream pharmaceutical markets because their pharmacological theories are different from those of modern medicine and their mechanisms of action are unclear[76]. Another important reason is that their pharmacological activities coexist with their toxicities, some of which are even greater than their pharmacological effects[77]. Nephrotoxicity is the most common toxic side effect of NPs, including electrolyte abnormalities, acute kidney injury, chronic kidney disease and even death[78]. For example, Tripterygium wilfordii has a variety of pharmacological effects[79]. However, Tripterygium wilfordii has shown serious toxic and side effects in clinical use, such as liver and kidney toxicity, male infertility, leukopenia, and menstrual disorders, especially liver injury[80]. More clinical trials and efficacy assessments are needed to develop strategies that minimize toxicity and adverse reactions when using NPs for treatment.