Cynanchum plants have been used to treat a variety of diseases in folk medicine, such as cancer, inflammation, and viral infections (Bailly, 2021; Chen et al., 2020; Zhou et al., 2020). C₂₁ sterol glycosides, a class of secondary metabolites in Cynanchum plants, are responsible for regulating cellular activities associated with cancer, including cell proliferation, apoptosis, and metastasis (Dong et al., 2020; Li et al., 2023a; Zhang L. et al., 2022). Among them, caudatin has attracted extensive attention from the scientific community due to its wide range of biological activities, especially its remarkable antitumor properties (Cheng et al., 2024; Peng Y. R. et al., 2008; Zhang M. et al., 2015). Currently, it has been recognized as a key phytochemical used in the treatment of various diseases (Li et al., 2022; Wang et al., 2021). Several studies have unraveled its potent anticancer, anti-inflammatory, and neuroprotective effects, which provide a promising direction for the development of novel therapeutic agents. Importantly, although others C₂₁ steroidal glycosides (e.g., dioscin) can have potent anticancer activity by triggering mitochondrial apoptosis, caudatin is structurally unique given its incorporation of an isovalerate side chain and the C-3 glycosylation affords a broader target specificity against Wnt/β-catenin and autophagy-lysosomal pathways. Unlike parthenolide (a sesquiterpene lactone known to inhibit NF-κB), caudatin had a better safety profile among preclinical studies and represents a useful scaffolding for structural analogue development.

At present, caudatin has been found to exhibit antiproliferative effects across various cancer cell lines, such as hepatocellular carcinoma (HCC), osteosarcoma, and breast cancer (Fei et al., 2019; Wang et al., 2024). Among them, the molecular mechanism against HCC was revealed to be related to the Wnt/β-catenin signaling pathway, which regulates the growth and differentiation of cancer cells (Luo et al., 2013). In addition, caudatin was found to modulate the inflammatory response and protect the nervous system, which highlights its multiple effects (Kim et al., 2024; Qiu et al., 2021). Of interest, SAR research has become a popular domain, resulting in several derivatives with enhanced bioactivity (Li X. S. et al., 2022; Wang et al., 2012a). Notably, pharmacokinetic studies have revealed that caudatin has a rapid clearance in vivo (Peng and Ding, 2015), which further supports its feasibility as a potential therapeutic agent (Peng Y. et al., 2008; Xu et al., 2007).

Caudatin has well-established bioactivity in numerous treatment areas such as strong anticancer activity through modulation of the Wnt/β-catenin pathway, anti-inflammatory activity through inhibition of JNK/NF-κB, and neuroprotective activity in Alzheimer’s disease; however, the literature lacks comprehensive review that collates caudatin’s structural, pharmacological, and translation characteristics. The need is critical because this void not only prevents a more complete understanding of caudatin’s multifunctional mechanisms but also draws a fine line on the logical development of caudatin derivatives for clinical application. The area of caudatin exploration is novel and fragmented, and this work attempts to fill this space as the first systematic review on caudatin, combining disparate evidence across disciplines to provide a comprehensive overview. We sought to encapsulate the structure-activity relationship, molecular targets, therapeutic applications, and safety profiling of caudatin into a single, unified document that builds on traditional, compound-specific reviews that typically only emphasize isolated biological effects. We hope this work builds a foundation to shed light on caudatin’s unique potential as a multi-functional drug scaffold, and catalyze further development from herbal medicine to modern therapeutics in oncology, neurodegeneration, and inflammation.

SAR refers to the correlation between structure and activity, and researchers can determine how changing the structure of a drug molecule affects its efficacy by analyzing this correlation (Choudhary et al., 2021; Khayat et al., 2023; Polishchuk, 2017). The study of SAR is significant for simplifying design, improving efficacy and effectiveness, and speeding up the development for new drugs (Cui et al., 2023; Ojha et al., 2021; Saganuwan, 2024).

A full understanding of its behavior in biological systems, essential for further caudatin development as a clinical agent, can only be achieved since the pharmacokinetic (PK) profile determines absorption, distribution, metabolism, and elimination (ADME), and parameters that control both safety and efficacy (McLachlan et al., 2020). In this section, we have reviewed the published studies on caudatin pharmacokinetics, specifically bioavailability, as well as metabolic limitations and ways to mitigate physicochemical limitations.

Quantitative characterization of the caudatin PK profile has been primarily derived from studies in rats, and particularly those that have successfully quantified using sensitive UPLC-MS/MS technology (Zhu et al., 2015) with a linear range established from 2.5 to 300 ng/mL in rat plasma. Following oral dosing of caudatin in normal rats, caudatin is absorbed rapidly, indicating it enters the systemic circulation promptly with a time to maximum plasma concentration (Tmax) of ∼ 0.29 h with maximum plasma concentration (Cmax) of 314.7  ± 82.0 Ã-g/L (Peng and Ding, 2015). This rapid movement into body circulation is a desirable quality and is likely an important contributor to the timing of efficacy. The rapid entry into circulation is favorable; however, this is coupled with the rapid elimination of caudatin observed in a short elimination half-life (t1/2) of about 1.25 h (Peng and Ding, 2015). This is further supported by a high apparent oral clearance (CL/F) of 80.8 ± 20.8 L/h/kg and large apparent volume of distribution (Vz/F) of 147.7 ± 78.0 L/kg, indicating extensive tissue distribution when considering the high systemic clearance. Interestingly, systemic exposure (AUC and Cmax) has also appeared to increase in a greater than dose-proportional manner, potentially indicating some degree of saturation of first-pass metabolism or other clearance pathways at high doses (Choules et al., 2024; Rodvold et al., 2020).

The pharmacokinetic profile of caudatin undergoes substantial modification in pathological states, particularly HCC. For example, studies using UPLC-MS show that caudatin appears to preferentially accumulate in the liver (Peng and Ding, 2015). When dosed in rats with diethylnitrosamine-induced HCC, systemic exposure increases dramatically when compared to healthy controls, and oral clearance significantly decreases. This strongly indicates that dysfunction of the cancerous liver has markedly reduced the first-pass elimination and as a result, there is substantial accumulation. This change is pharmacologically significant: increased concentration at the site of action in the denominated disease state could increase its efficacy as a therapeutic for HCC, making caudatin an attractive drug for liver disease place of action. However, this could also mean safety issues due to the potential for high drug exposure to patients with poor liver function leading to toxicity.

However, despite this, there are significant knowledge gaps that will prevent the rational development of caudatin. One serious knowledge gap is pharmacokinetics data related to the absolute oral bioavailability of caudatin. Oral bioavailability, which is the measure of drug exposure in systemic circulation following oral dosing compared against IV dosing using AUC calculation, is critical to understanding if low systemic concentration comes from either poor absorption, first pass metabolism, or both (Yang et al., 2012). Although the high CL/F strongly indicates it has a low systemic availability, we cannot fully understand root cause, e.g., poor membrane permeability, low aqueous solubility, high first pass metabolism in gut wall and liver, etc. without an IV study (Tang et al., 2017). Furthermore, drug exposure reflected in oral bioavailability is greatly influenced by formulation, route of administration, and in vivo stability; poorly soluble caudatin presents added risk for oral absorption and formulation considerations (Zhang et al., 2023). Contributing to this is a lack of information regarding the in vivometabolic fate of caudatin itself. There are no reports in the literature on the identification or structural elucidation of its Phase I (e.g., hydroxylation, oxidation, reduction, hydrolysis of the glycosidic bond) or Phase II (e.g., glucuronidation, sulfation) metabolites. A preliminary study using UPLC-MS/MS with metabolynx software investigated a derivative, caudatin 2,6-dideoxy-3-methyl-β-D-cymaropyranoside, in human intestinal mucosal epithelial cells (Zhang M. et al., 2015). This work suggested the involvement of metabolic pathways such as hydrolysis, oxidation, and methylation, and indicated there was a relatively high metabolic capacity therefore likely leading to the biological effects they reported. Nonetheless, there is no in vivo metabolite profiling for the parent caudatin compound. Without identification and characterization of these metabolites, it is not possible to assess their pharmacological activity, inactivity, or possible toxicities as well as potentially identify which enzymes are responsible for their clearance, which is necessary to predict possible drug-drug interactions.

Consequently, the available literature has provided a preliminary, but incomplete, pharmacokinetic profile for caudatin. The data confirms caudatin’s rapid absorption and extensive elimination, and intriguing and putative therapeutic beneficial pharmacokinetic changes in liver disease which result in higher hepatic exposure. While this is indicative of promise as an anti-hepatocellular carcinoma agent with an inherent hepatic targeting component, future progress is stunted by the lack of data on absolute bioavailability, the dearth of studies specifically targeted at addressing formulation issues and the comprehensively absence of any type of in vivo metabolic profiling. Addressing the gaps in knowledge in each of these areas is critical: future research needs to prioritize conducting IV studies to definitively calculation bioavailability, also followed by thoroughly testing novel formulation approaches (for example,; cyclodextrin complexation, nano-formulations, prodrugs) which take into account the existing solubility issues and absorption issues respectively, while utilizing current techniques like LC-MS/MS-high resolution mass spectrometry (HRMS) to systematically determine the context of the in vivo metabolism of caudatin and define it's metabolites (Rocha et al., 2023; Stielow et al., 2023). It is only by addressing these major knowledge gaps that caudatin’s pharmacological potential can be properly evaluated. Furthermore, such information is critical to advance a natural product into a therapeutic candidate for HCC, but potentially also other conditions such as inflammation, muscular dystrophy and neurodegeneration.

In vitro and in vivo studies on the toxicity of caudatin have shown that it exhibits a relatively low toxicity profile in terms of its therapeutic efficacy (Figure 6). Here are some detailed examples.

This review highlights the therapeutic viability of caudatin from structural optimization, pharmacological mechanism, and clinical implications, suggesting it as a multi-facilitive scaffold for drug discovery. Caudatin is derived from plants of the genus Cynanchum and has been found to have strong anticancer efficacy by modulating Wnt/β-catenin, NF-κB, and PI3K/AKT pathways, inducing ROS-mediated apoptosis, and inhibiting metastasis through the inhibition of epithelial to mesenchymal transitions. Caudatin’s anti-inflammatory effects target JNK/AP-1 and NF-κB cascades, while neuroprotective effects with reduced Aβ in an Alzheimer’s model occur due to PPARα/TFEB-driven autophagy. The SAR studies uncovered evidence of C-3 hydroxyl groups as critical for facilitating bioactivity and pharmacokinetics through modifications (e.g., esterification with nitrogen heterocycles or glycosylation). Since caudatin is quickly absorbed, preferentially taken up by the liver, and has a favorable safety profile, it connects centuries of traditional medicine to modern therapeutics. Future advances, including derivatives of caudatin optimized using artificial intelligence, smart delivery systems, and demonstrating translatability will be pivotal for overcoming bioavailability limitations, and instigating the translational potential of caudatin to combat cancer, neurodegeneration, and inflammation.

Increasing evidence of caudatin’s diverse pharmacological activities suggest potential as a starting point for drug development. However, addressing critical challenges and opportunities are needed to translate preclinical promise into a new therapeutic.

Advanced drug delivery systems provide opportunities to mitigate caudatin’s toxicity and bioavailability shortcomings by improving solubility with nanocarrier platforms (liposomes or polymer nanoparticles utilizing the EPR effect for tumor-specific delivery), decreasing overall exposure to the liver and kidneys; e.g., in their liver targeted formulations, the concentration in the liver was increased 3.2-fold and kidney distribution decreased by 40% (Peng and Ding, 2015); improving safety profiles with prodrug constructs that functionalize the C-3 hydroxyl group with hydrophilic moieties (e.g., like PEG/amino acids), expand therapeutic windows, e.g., prodrug derivatives that increase HepG2 IC₅₀ from 22.5 µM to 58.3 µM (Tao et al., 2015); and restricting drug release to target tissue non-systemically with stimuli-responsive carriers (pH or ROS-dependent systems) that exploit tumor microenvironments to limit systemic toxicity and subsequent Bax/Bcl-2 dysregulation in normal cells (Fei et al., 2012b).

The systematic analysis of SAR will be an important breakthrough to advance the structure optimization of caudatin. Through targeted modification of its parent core structure, researchers have found that the introduction of specific functional groups can significantly enhance bioavailability while maintaining the core pharmacological activity (Huang et al., 2016). While previous C-3 modifications enhance bioactivity, systematic SAR studies have been limited for not properly targeting the right modifications. Although the nitrogen heterocycles at the C-3 position increased cytotoxicity, the advantages of membrane permeability versus solubility were not established. Using in silico methods of molecular docking to map steric/electronic requirements of binding pockets in biological targets could systematically elucidate appropriate rational designs (Pinzi and Rastelli, 2019). Moreover, halogenation at the cinnamoyl moiety increased antiviral activity, there is evidence that supplemental electronegative groups to increase target affinity across diseases is achievable (Rivas-Urbina et al., 2019). On the other hand, an undue focus on optimizing the C-3 position may come at the expense of other pharmacophore regions such as the rigid steroidal core and the C-20 keto group, which are also important structural stability and target binding determinants, and have not been investigated deeply either. This imbalance may also limit overall efficacy and stability of the drug, which affects its therapeutic efficacy and subsequent clinical application of the drug. Therefore, the contribution of each part of the molecule should be evaluated in a more holistic view when designing drugs.

Preclinical studies are urgently needed to validate caudatin’s efficacy in a wider range of cancer models and inflammatory diseases (Dong et al., 2022; Peng and Ding, 2015; Seddiki and French, 2021). In vitro and in vivo studies may suggest or provide a useful degree of efficacy, but do not provide a complete representation of the clinical heterogeneity present in human disease. To our knowledge, there have been no clinical studies that have examined caudatin or its derivatives, because it is currently still in pre-clinical research. A few key issues represent the bottleneck to it becoming clinically useful - which we outline below. First, there are challenges to bioavailability, which would involve rapid systemic elimination or possible solubility issues, as highlighted in preclinical pharmacokinetic studies (Peng and Ding, 2015). Second, there is a lack of long-term safety data (especially for organ-specific effects, e.g., liver or kidneys), despite preclinical safety data being promising! Third, there does need to be some innovative formulation methods (e.g., nanoparticle delivery systems, prodrugs, etc.) from a tissue-targeting and stability perspective, as discussed regarding future research directions. Fourth, because of its multitarget mechanisms of action, dose optimisation must be approached carefully in order to assess therapeutic versus off-target effects. We would recommend that the primary effort be given to standardised Phase I clinical trials to assess safety and pharmacokinetics first. Following this, Phase II and Phase III multi-centre trials can be designed to test effectiveness in a specific area, such as cancer or neurodegenerative disorder. Rigorous clinical trials are essential for elucidating optimal dosing regimens, assessing safety profiles, and determining therapeutic efficacy in humans (Liu et al., 2021; Umscheid et al., 2011). On this basis, a standardized phase I clinical study should be conducted to develop a precise dosing regimen. Then, a multicenter phase II/III clinical trial will be conducted to clarify the efficacy of the drug in specific indications. This stepwise research strategy will effectively promote caudatin from laboratory to clinical practice. In like manner, while caudatin presents anti-inflammatory and neuroprotective properties in Alzheimer’s disease models, translation to humans will be more complex and we ultimately need to consider whether there are ways caudatin can pass the selective permeability of the blood-brain barrier. This will probably be done with nanoparticle-based delivery systems or prodrug-based formulations in the future.

Safety assessments of caudatin derivatives have offered assurance, but limited data are available on their long-term toxicity. It is important to recognize that while past SAR studies have identified relevant modification positions using empirical methods, there has not been any effort to apply the advanced tools of artificial intelligence (AI) or machine learning (ML) to the structural derivatization of caudatin. However, AI/ML tools can be revolutionary in accelerating and streamlining optimization processes: In cases where we compute ADMET (absorption, distribution, metabolism, excretion, and toxicity) models to predict analogues’ pharmacokinetics and potential safety issues, thus allowing us to vet based on low-risk candidates; deep learning can represent a target protein’s spatial/electronic requirements, allowing for rational multipoint modification beyond the C-3 position; and, we can also deploy fragment-based generative models to apply generative chemistry to de novo design new scaffolds based upon the known caudatin pharmacophores and bioactive fragments (Gupta et al., 2021). We currently have bottlenecks with not having sufficient quality in 1vivo data to train models; the complexities of deriving and modeling multi-target interactions; and the synthetic feasibility of structures suggested by AI. The path to overcoming these challenges should include using existing SAR data in order to build an open-source dataset and designing hybrid models that incorporate quantum mechanics-calculations to ML to systematically derive design that covers all three compounds. If we include AI and ML used in SAR studies, caudatin derivatives could be optimized quicker by predicting binding affinities and their ADMET properties; this should limit the use of empirical trial-and-error methods. Eventually, it will be necessary to collaborate with researchers working in pharmacology, bioengineering, and clinical medicine to evolve caudatin into a clinically proven therapeutic from a phytochemical, laying the foundation for precision medicine.