A primary anti-cancer strategy of AE is to halt the continuous proliferation of cancer cells by inducing cell cycle arrest (Zhou et al., 2024). It primarily accomplishes this by down-regulating the expression or activity of cell cycle proteins, including Cyclin D1, B1, and their cyclin-dependent kinases (CDKs), so obstructing the cell cycle at the G1/S or G2/M transition stages (Kung et al., 2025; Witkiewicz et al., 2022; Niu et al., 2023). Concurrently, AE is a powerful inducer of apoptosis. It can concurrently activate both the internal mitochondrial and extrinsic death receptor apoptotic pathways (Zhang W. et al., 2023). It often enhances the expression of the tumor suppressor protein p53, thereby modulating the Bcl-2 protein family by elevating the ratio of pro-apoptotic members, such as Bax and Bak, to anti-apoptotic members, such as Bcl-2 and Bcl-xL (Hao et al., 2023; Wei et al., 2023; Wei et al., 2021). This disturbs the mitochondrial membrane potential, resulting in the release of cytochrome c, which then activates the Caspase protease cascade, thus executing the cell death program (Zhang X. et al., 2023) (Figure 1).

Autophagy is a cellular self-digestion mechanism that serves a context-dependent dual function in cancer. The relationship between autophagy and AE is similarly intricate, like to a “double-edged sword”. In certain cancer types, AE can trigger cytotoxic autophagy, resulting in autophagic cell death and thereby amplifying its anti-cancer efficacy (Huang et al., 2021; Li R. et al., 2025; Wu JJ. et al., 2024). Under different conditions, it may impede protective autophagy, which cancer cells employ to withstand stress and chemotherapy (Huang et al., 2023; Zhu et al., 2021). Consequently, the inhibition of autophagy can enhance the susceptibility of cancer cells to alternative therapies. The molecular switches governing this duality often encompass the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathways (Wang H. et al., 2022; Bahar et al., 2024; Xu et al., 2025). Activation of AMPK or inhibition of mTOR by AE can induce autophagy; nevertheless, the fate of the cells whether they perish or endure depends on the particular cellular milieu and the magnitude of the autophagic flux (Paquette et al., 2021).

The predominant cause of cancer-related mortality is tumor metastasis. AE exhibits considerable anti-metastatic efficacy by targeting critical phases in the metastatic cascade (Qu et al., 2025; Jiang et al., 2021; Şeker et al., 2022). Research indicates that it can inhibit the function of matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, which are essential for extracellular matrix degradation and facilitating cancer cell invasion (Şeker et al., 2022). Furthermore, AE can reverse the epithelial-mesenchymal transition, a process wherein cancer cells lose epithelial traits and gain migratory and invasive capabilities. AE accomplishes this reversal by up-regulating epithelial markers such as E-cadherin while down-regulating mesenchymal markers like N-cadherin and Vimentin (Chen et al., 2023). Additionally, AE impedes tumor growth by inhibiting angiogenesis, primarily by suppressing the expression and signaling of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Hassan et al., 2024; Dai et al., 2025).

The tumor microenvironment (TME) is a multifaceted ecosystem consisting of cancer cells, immune cells, fibroblasts, and signaling molecules, which significantly affects tumor growth and therapeutic response (Chen X. et al., 2025). AE is becoming a potent modulator of TME. It can “re-educate” pro-tumorigenic M2 type tumor-associated macrophages to polarize into the anti-tumor M1 phenotype (Shah et al., 2022). This change aids in reactivating local anti-cancer immune responses (Li X. et al., 2024). Moreover, by inhibiting pro-inflammatory cytokines like IL-6 and TNF-α in the TME, AE can mitigate chronic, tumor promoting inflammation and modulate the activities of other immune cells, including T cells and dendritic cells, thus establishing a microenvironment detrimental to tumor proliferation (Qu et al., 2025; Yin et al., 2025).

Acquired or intrinsic medication resistance is a significant challenge in cancer chemotherapy. AE, as a chemical sensitizer, has demonstrated significant potential in restoring or augmenting the potency of conventional anticancer agents (Cheng et al., 2021). A primary mechanism is the inhibition of ATP binding cassette transporters, including P-glycoprotein, which function as “drug pumps” to extrude chemotherapeutic drugs from cancer cells (Yoganathan et al., 2021; Moinul et al., 2022; Sun et al., 2025). By inhibiting these pumps, AE enhances the intracellular retention of medicines like as cisplatin, doxorubicin, and paclitaxel (Hanssen et al., 2021; Liang et al., 2021). It can resensitize drug resistant cells by modulating the dysregulated signaling pathways that contribute to resistance, therefore reinstating their apoptotic capability (Bharathiraja et al., 2023). This renders AE a particularly effective adjunctive medication in combination therapy protocols (Liang et al., 2021).

The anti-inflammatory efficacy of AE is primarily ascribed to its potent suppression of various established pro-inflammatory signaling pathways. It can effectively inhibit the activation of NF-κB, a principal transcription factor that governs the expression of several inflammatory genes (Wang WB. et al., 2022; Shang et al., 2022). AE generally sequesters NF-κB in the cytoplasm by inhibiting the degradation of the NF-κB inhibitor IκBα (Li H. et al., 2025; Shen et al., 2024). Furthermore, it can obstruct the phosphorylation and activation of the mitogen-activated protein kinase (MAPK) pathway, encompassing p38, ERK, JNK, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, both of which are pivotal in orchestrating inflammation and immune responses (Lu et al., 2025).

Oxidative stress, resulting from the disparity between reactive oxygen species (ROS) production and the cellular antioxidant defense mechanism, is intricately linked to inflammation (Song et al., 2022). AE functions not only as a direct ROS scavenger but also exerts a significant antioxidant effect indirectly (Ren et al., 2024). The primary indirect method is the stimulation of the nuclear factor erythroid 2-related factor Nrf2 pathway (He et al., 2023). AE facilitates the translocation of Nrf2 to the nucleus, consequently upregulating the expression of various antioxidant and cytoprotective genes, including heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1(NQO1), which enhances the cellular intrinsic defense against oxidative damage (Ouyang et al., 2024).

In the domain of neurodegenerative disorders, AE has exhibited encouraging neuroprotective properties (Yan et al., 2023). In preclinical Alzheimer’s disease models, it has been shown to impede the aggregation of β-amyloid protein and diminish the hyperphosphorylation of Tau protein, both of which are critical pathological indicators of the disease (Li X. et al., 2024). In Parkinson’s disease models, AE can safeguard dopaminergic neurons from neurotoxin-induced apoptosis, partially due to its robust anti-inflammatory and antioxidant effects, which mitigate the chronic neuroinflammation propelling disease advancement (Mitra et al., 2022; Xian et al., 2021).

AE has broad-spectrum antimicrobial activity. It has been proven effective against a range of enveloped viruses, including influenza virus, herpes simplex virus, coronavirus, etc (Wu J. et al., 2024). Its mechanism of action is usually to interfere with the virus’s entry, attachment or replication process (Li Z. et al., 2024). Its antibacterial effect has been reported in both Gram-positive and Gram-negative bacteria. Possible mechanisms include disrupting the bacterial cell membrane, inhibiting nucleic acid synthesis, and interfering with the bacterial quorum sensing system (Hu et al., 2023).

Initial research indicates that AE may have a positive impact on metabolic disorders. In animal models of type 2 diabetes and obesity, AE has demonstrated enhancement of insulin sensitivity, reduction of blood glucose levels, and mitigation of lipid buildup in hepatic and adipose tissues (Ouyang et al., 2024). Certain effects are thought to be facilitated by the activation of AMPK, a fundamental regulator of cellular energy metabolism, which intersects with its mechanisms in cancer and autophagy (Bao et al., 2024; Yu et al., 2023). These findings present a novel opportunity for investigating the application of AE in the management of metabolic syndrome.

As stated in Section 2.1.5, AE is a powerful chemical sensitizer, and its synergistic effects with standard chemotherapeutic drugs like cisplatin, doxorubicin, and paclitaxel are well-documented in the literature (Dai et al., 2025). This synergy is accomplished through various mechanisms: AE enhances the intracellular retention of chemotherapeutic agents by blocking efflux pumps like P-glycoprotein and reinstates the sensitivity of drug-resistant cancer cells to apoptosis through the modulation of p53 or Bcl-2 family proteins (Qu et al., 2025; Chen et al., 2023; He et al., 2023; Li X. et al., 2024). Simultaneously, the potent anti-inflammatory and antioxidant characteristics of AE can mitigate the severe side effects of chemotherapy, including organ damage from nephrotoxicity or cardiotoxicity, thus improving patients’ tolerance to treatment and potentially facilitating the implementation of more effective dosing regimens (He et al., 2023; Li X. et al., 2024).

The integration of the immunomodulatory properties of AE with novel cancer immunotherapies constitutes a particularly promising domain. Immune checkpoint inhibitors, including antibodies that target PD-1 or PD-L1, have transformed cancer therapy (Yang et al., 2025); yet, their effectiveness is frequently restricted to patients with pre-existing T-cell infiltration within their tumors (Kim et al., 2025). The capacity of AE to alter the tumor microenvironment presents a compelling approach for transforming immunologically “cold” malignancies into “hot” cancers. By converting M2-type macrophages to the M1 phenotype, mitigating chronic inflammation, and potentially augmenting antigen presentation, AE might establish a more conducive tumor microenvironment for T-cell activation and invasion (Gao et al., 2025). This TME “reprogramming” is anticipated to synergize with ICIs, surmounting primary or acquired resistance and thereby broadening the patient pool that benefits from these groundbreaking medicines (Pich-Bavastro et al., 2023; Ye et al., 2024). This burgeoning field offers significant potential for future cancer therapy approaches.

The primary impediment obstructing the therapeutic advancement of AE is its inadequate “druglikeness,” particularly regarding its pharmacokinetic properties. A characteristic attribute of AE is its markedly low water solubility, which significantly limits the options for its formulations and its dissolving within the gastrointestinal tract (Ai et al., 2025; Xu et al., 2023). Following oral ingestion, it experiences significant first-pass metabolism in the liver and intestinal wall, primarily by glucuronidation and sulfation, and is swiftly digested (Ren et al., 2024; El-Say et al., 2023; Kumar et al., 2024). The synergistic impact of inadequate absorption and accelerated metabolism results in exceedingly low oral bioavailability, often ranging from 1% to 5%, complicating the attainment and maintenance of an effective plasma therapeutic dosage via standard oral administration (Xie et al., 2023; Sulistiawati et al., 2024).

AE shares many pharmacokinetic features with other plant-derived anthraquinones. Anthraquinones are absorbed mainly in the intestines, where free aglycones exhibit faster absorption than their glycosidic forms due to greater liposolubility; nonetheless, AE generally displays low oral bioavailability and considerable inter-individual variability (Wang et al., 2021). Anthraquinones frequently exhibit variable plasma concentration-time profiles characterized by several absorption peaks, owing to hepato-intestinal circulation, reabsorption, and dynamic interconversion among various anthraquinone molecules. Subsequent to absorption, they are extensively disseminated to tissues with abundant blood supply, such as blood, the gastrointestinal system, liver, lungs, kidneys, and adipose tissue. Significantly, AE can be transformed into other anthraquinones, including rhein and emodin, and may also originate from their metabolism, indicating that systemic exposure can be more accurately represented by its metabolites than by the parent substance. The primary excretion pathways for anthraquinones include renal, biliary, and fecal. The pharmacokinetic attributes-site-specific intestinal absorption, significant first-pass metabolism and interconversion, and swift excretion-elucidate the low or undetectable plasma levels of AE noted in clinical and preclinical studies, highlighting the necessity to assess both parent AE and its metabolites in evaluating efficacy and safety.

The multi-target pharmacological properties of AE (Yan et al., 2023; Ouyang et al., 2024; Qu et al., 2025), specifically its capacity to engage with several targets, present a double-edged sword. This foundation for its success in complex, multifactorial disorders also raises questions regarding selectivity and potential off-target effects (Wang Z. et al., 2025; Ren et al., 2024). The absence of a singular, highly specific target presents obstacles for the design of pharmacodynamic biomarker studies and the prediction of its comprehensive biological effects (Ren et al., 2024; Dai et al., 2025). This “pan-targeting” may result in unforeseen side effects, particularly with prolonged use, complicating the safety profile necessary for clinical approval (He et al., 2023; Chen S. et al., 2025).

While typically regarded as safe at low dosages, particularly when ingested as a conventional herbal element, pure AE has demonstrated measurable hepatotoxicity and nephrotoxicity at relatively high experimental doses in certain investigations (Ren et al., 2024). The primary concerns are hepatotoxicity and nephrotoxicity, reported in animal models subjected to elevated doses (e.g., tens to hundreds of mg/kg/day of purified AE) or prolonged exposure (Li X. et al., 2024; Wang S. et al., 2025). The dose-dependent toxicity, coupled with the necessity of administering high dosages to offset its low bioavailability, results in a potentially small “therapeutic window”—the interval between the effective dose and the dangerous dose (Dai et al., 2025). Defining and sustaining drug exposure within this interval is a significant hurdle for its safe clinical application, necessitating meticulous dose exploration investigations and potentially therapeutic drug monitoring (Qu et al., 2025).

A systematic search of the Cochrane Library (search terms: “aloe-emodin”) did not identify any Cochrane systematic reviews or registered randomized trials focusing on aloe-emodin as a single pharmacological agent. Existing clinical data are therefore derived from small-scale trials and observational studies, many of which evaluate multi-component preparations containing AE rather than purified AE alone. These studies, including the pharmacokinetic investigation “Rhein and aloe-emodin kinetics from senna laxatives in man” (Krumbiegel and Schulz, 1993), which assessed clinically used doses of senna based laxatives in healthy volunteers, suggest potential utility in the context of laxative therapy but also highlight important limitations: aloe-emodin itself was not detectable in plasma at any sampling point, whereas its related anthraquinone rhein reached peak concentrations of approximately 150–160 ng/mL with biphasic maxima at 3–5 h and 10–11 h after dosing, likely reflecting absorption of free rhein and rhein released from prodrugs by colonic bacterial metabolism. These findings indicate that, under clinically used laxative regimens, systemic exposure to free AE appears to be minimal, and the observed effects are largely mediated by other anthraquinone derivatives or their metabolites. Overall, the clinical evidence remains preliminary and is limited by small sample sizes, heterogeneous study designs, and the difficulty of attributing efficacy and safety profiles specifically to aloe-emodin within multi-component herbal preparations.