Future Pharmacology

Background: Inflammatory bowel disease (IBD) is defined as recurrent inflammatory bowel disorders, the most common of which are Crohn’s disease (CD) and ulcerative colitis (UC). Tumor necrosis factor inhibitors (anti-TNFs), primarily adalimumab (ADA), infliximab (IFX), ustekinumab (UST), and vedolizumab (VLZ), are used to treat moderate-to-severe cases of IBD in patients who either do not tolerate or fail to respond to conventional therapies. However, about one-third of patients are primary non-responders to these treatments, and an additional 30% lose response over time. Several studies have investigated the role of genetic variability in explaining these differences in treatment response among patients. The aim of this study was to design an array of 60 single-nucleotide variants (SNVs) to validate the biomarkers described in the literature in a population of more than 400 IBD patients treated with biological drugs. Method: The primary focus of this study was the most recent reviews published in PubMed, with all relevant SNVs selected for the array design. Subsequently, studies presenting original data on the association between variants and the response to biological treatment were identified. Results: A total of 55.9% of SNVs have been studied in CD, 18.6% have been in UC, and 25.4% have been studied in both pathologies. A total of 44.1% of SNVs have been observed to influence the response to IFX, 16.9% influence the response to ADA, and 37.3% influence the response to both IFX and ADA; however, only one study (1.7%) reported an influence on the response to UST and none reported an influence on the response to VLZ. Conclusions: An array comprising 38 genes and 59 SNVs has been designed to be used to validate biomarkers associated with responses to biologic drug treatments in IBD. Full article

Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies. Drug repurposing offers a cost-effective approach to cancer treatment by identifying new anticancer applications for existing drugs. Terbutaline, a β2-adrenergic receptor agonist, and Milrinone, a phosphodiesterase-3 inhibitor, are traditionally used as positive inotropic agents but have shown potential anticancer effects. This review explores their mechanisms of action in cancer, focusing on their roles in modulating cyclic adenosine monophosphate (cAMP) levels, oxidative stress, and the tumor microenvironment. Terbutaline influences β2-adrenergic signaling, impacting cell proliferation, angiogenesis, and immune evasion. Milrinone, through PDE3 inhibition, elevates cAMP, promoting apoptosis and reducing tumor growth. Both agents exhibit anti-inflammatory and anti-angiogenic properties, suggesting their potential as adjuvant therapies in oncology. Despite promising preclinical data, clinical validation is required to confirm their efficacy and safety in cancer patients. This review highlights the therapeutic promise of repurposing Terbutaline and Milrinone, emphasizing the need for further research to optimize their application in cancer therapy. Full article

Recently, a number of new genes (NFE2L2, HFE, HMOX, HIF-1α, ALOX5, GPX4, PTGS2, and IL-6) have been recognized as playing a role in ferroptosis and genetic predisposition to cardiovascular diseases (CVDs). Identifying these novel genes may facilitate the discovery of therapeutic agents and improve the clinical evaluation of phenotypes and prognoses in CVD patients. In the future, it will be crucial to develop genetic markers that correlate with clinical outcomes for individuals with CVDs. This review highlights recent developments in ferroptosis research while interpreting how genetic factors may contribute to the pathogenesis of CVDs. Understanding this relationship could be invaluable for predicting disease progression in individual patients, informing suitable medical interventions, and facilitating early diagnosis and treatment. Furthermore, we examine the possible uses of these disorders in diagnosis and the various treatment strategies, along with the associated challenges and existing limitations. Full article

The success of checkpoint inhibitors in improving cancer patient survival has demonstrated the therapeutic potential of immunotherapies. This advancement has reshaped oncology treatment and driven interest in harnessing immune modulation for a wider range of diseases. However, developing drugs that modulate immune activity presents unique challenges. A major limitation in preclinical research is the inefficiency of testing human-specific immune targets in animal models, which often fail to translate to clinical outcomes. Additionally, conventional in vitro systems lack immune reactivity due to their static and monocellular nature, limiting their predictive value. Advanced in vitro models can bridge this gap by offering increasingly relevant human physiology for testing drug efficacy and safety, along with absorption, distribution, metabolism, and excretion (ADME). In particular, immune-competent spheroids, organoids, and organs-on-a-chip (OoC) have emerged as promising tools. Although still in their infancy, these microphysiological systems (MPSs) have demonstrated the feasibility of replicating immune responses ex vivo, providing a new avenue for studying immune-targeting drugs with higher translational potential. In this review, we explore recent advances in immune-competent organoid and OoC models, highlighting their capabilities and limitations. We provide a perspective on their applications for cancer drug testing, discussing how these systems could refine preclinical immuno-oncology research and accelerate the development of next-generation immunotherapies. Full article

Biofilm-associated infections caused by Gram-negative bacteria, especially multidrug-resistant strains, frequently occur in intensive care units and represent a major therapeutic challenge. The economic burden of biofilm-associated infections is considerable, making the search for new treatment approaches a focal point for policymakers and scientific funding bodies. Biofilm formation is regulated by quorum sensing (QS), a population density-dependent communication mechanism between cells mediated by small diffusible signaling molecules. QS modulates various intracellular processes, and some features of QS are common to all Gram-negative bacteria. While there are differences in the QS regulatory networks of different Gram-negative bacterial species, a common feature of most Gram-negative bacteria is the ability of N-acylhomoserine lactones (AHL) as inducers to diffuse across the bacterial membrane and interact with receptors located either in the cytoplasm or on the inner membrane. Targeting QS by inhibiting the synthesis, transport, or perception of signaling molecules using small molecules, quorum quenching enzymes, antibodies, combinatorial therapies, or nanoparticles is a promising strategy to combat virulence. In-depth knowledge of biofilm biology, antibiotic susceptibility, and penetration mechanisms, as well as a deep understanding of anti-QS agents, will contribute to the development of antimicrobial therapies to combat biofilm infections. Advancing antimicrobial therapies against biofilm infections requires a deep understanding of biofilm biology, antibiotic susceptibility, penetration mechanisms, and anti-QS strategies. This can be achieved through in vivo and clinical studies, supported by state-of-the-art tools such as machine learning and artificial intelligence. Full article

The tumor microenvironment (TME) is crucial for the onset, development, and resistance to treatment of lung cancer. The tumor microenvironment consisting of a complex array of immune cells, fibroblasts, endothelial cells, extracellular matrix elements, and signaling molecules, facilitates tumor growth and spread while inhibiting the body’s antitumor immune response. In lung cancer, tumor-associated macrophages, cancer-associated fibroblasts, mast cells, and dendritic cells interact through cytokines, chemokines, growth factors, and matrix metalloproteinases to create an immunosuppressive and proangiogenic milieu. Hypoxic conditions within the TME further enhance cancer cell adaptability through hypoxia-inducible factors (HIFs), promoting epithelial–mesenchymal transition, immune evasion, and metastasis. Moreover, miRNAs have emerged as key regulators of gene expression within the TME, offering novel insights into tumor behavior and potential therapeutic targets. Targeting dynamic interactions within the TME, particularly through the modulation of immune responses, angiogenesis, and stromal remodeling, offers promising avenues for precision pharmacological approaches. This review covers the current understanding of the lung TME, highlighting its impact on cancer pathophysiology and treatment strategies. Understanding and therapeutically reprogramming the TME may pave the way for personalized and more effective interventions for lung cancer treatment. Full article

Objective: This study evaluated the systemic bioavailability of L-thyroxine (L-T4) in healthy women following repeated cutaneous application of a new gel formulation containing L-T4 and escin. Plasma concentrations of free triiodothyronine (FT3), reverse triiodothyronine (rT3), and thyroid-stimulating hormone (TSH) were also assessed, along with local and systemic tolerability. Methods: Thirty healthy women participated in a single-group, open-label trial. L-thyroxine gel was applied at 20 g/day for the first 2 days and 10 g/day for the following 26 days (equivalent to 20 mg/day and 10 mg/day of L-T4, respectively). Blood samples were collected at Baseline, 5 and 24 h after the first application, and on Days 14, 28 (End of Treatment, EOT), and 42 (End of Study, EOS). Tolerability and safety were monitored throughout. Results: Plasma FT4 concentrations remained stable throughout the study, with no clinically significant changes from Baseline (1.13 ± 0.15 ng/dL) to EOT (1.11 ± 0.13 ng/dL). FT3 and TSH levels also remained within physiological ranges, with only a transient, non-clinically relevant decrease observed 5 h after the first application. No changes in rT3 concentrations were detected at any time point. No serious adverse events were reported. Conclusions: This study confirms that repeated application of L-thyroxine/escin gel over 28 days (total exposure of 300 g) does not affect systemic thyroid hormone levels and is well tolerated in healthy women. These findings support the hypothesis that intact skin acts as an effective barrier to transdermal L-T4 absorption. Full article

Bacterial natural ecological niches are characterized by variations in the availability of nutrients, resulting in a complex metabolism. Their impressive ability to adapt to changeable nutrient conditions is possible through the utilization of large amounts of substrates. Recent discoveries in bacterial metabolism have suggested the importance of polyamine metabolism in bacteria, particularly in those of the order Actinomycetales, in enabling them to survive in their natural habitats. This makes such enzymes promising targets to inhibit their growth. Since the polyamine metabolisms of soil bacteria of the genus Streptomyces and the human pathogenic Mycobacteria are surprisingly similar, target-based drug development in Streptomyces and Mycobacterium spp. is an alternative approach to the classical search for antibiotics. The recent development of drugs to treat epidemic diseases like tuberculosis (TB) has gained attention due to the occurrence of multidrug-resistant strains. In addition, drug repurposing plays a crucial role in the treatment of various complex diseases, such as malaria. With that notion, the treatment of TB could also benefit from this approach. For example, molecular chaperones, proteins that help other proteins to fold properly, are found in almost all living organisms, including the causative agents of TB. Therefore, targeting these molecules could help in the treatment of TB. We aim to summarize our knowledge of the nitrogen and carbon metabolism of the two closely related actinobacterial genera, Streptomyces and Mycobacterium, and of the identification of new potential drug targets. Full article

Background and Aim: Neuropathic pain leads to a significant deterioration in health-related quality of life (HRQOL). Treating neuromusculoskeletal pain is especially important to prevent and improve physical frailty and the locomotive syndrome. Varied pharmacotherapies could be applicable for neuropathic pain patients, but evidence has been limited for a wide range of neuropathic pain conditions with different etiologies. The aim of this review was to highlight mirogabalin, a novel calcium channel α2δ ligand which was first approved in Japan, and which is effective for various types of neuropathic pain diseases. Methods: We conducted a narrative review of the recent evidence that mirogabalin has significant analgesic potency for varied types of neuropathic pain conditions. Futher, this review highlighted specific advantages over other calcium channel ligands. Results: Analgesic potency of mirogabalin could cover peripheral neuropathic pain conditions including post-herpetic neuralgia, diabetic peripheral neuropathy, cauda equina syndrome caused by lumbar spinal stenosis, radiculopathy caused by cervical spondylosis, and also central neuropathic pain conditions like spinal cord injury. Mirogabalin consistently demonstrated daytime sleepiness and dizziness as adverse effects, but most of these were mild. Conclusions: Mirogabalin is recommended as the first-line drug against most molecular mechanisms that cause neuropathic pain regardless of whether they have a peripheral or central origin. Mirogabalin demonstrates relatively less daytime sleepiness, making it age-friendly in the current global situation where population aging is accelerated. Considering the epidemic of ‘opiophobia’ in Japan and other countries, pharmacotherapy using mirogabalin could treat neuropathic pain associated with cancer and its treatment (e.g., chemotherapy-induced peripheral neuropathy), as well as non-cancer etiologies worldwide. Full article

Osteoarthritis (OA) is a multifactorial, degenerative joint disease that significantly impairs mobility and quality of life, especially among older adults. The growing aging population and increasing obesity rates are expected to increase the incidence and prevalence of OA. In the absence of Disease-Modifying Antirheumatic Drugs (DMARDs) for OA, current treatment strategies largely focus on symptom relief rather than disease modification. These symptomatic treatments often fail to account for the substantial inter-individual variability in drug response. Pharmacogenomics (PGx), the study of how genetic variation influences drug response, offers a promising approach to personalize OA therapy. This review explores the clinical and pharmacogenomic considerations of commonly used OA medications—acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol—focusing on gene–drug interactions that influence efficacy, safety, and metabolism. Evidence-based recommendations from the Clinical Pharmacogenetics Implementation Consortium guidelines are discussed, where applicable, to highlight actionable genetic variants in very important pharmacogenes such as CYP2D6, CYP2C9, and other important drug-metabolizing encoding genes such as CYP2E1 and UGT1A6. While PGx data are not currently embedded in OA clinical treatment guidelines, their integration into clinical practice may enhance therapeutic outcomes and minimize adverse drug events. This review underscores the potential of PGx as a clinical tool in OA pain management, paving the way toward truly personalized medicine. Full article

Algal polysaccharides are a kind of bioactive compound with diverse pharmacological applications, yet their structure–activity relationships and therapeutic potential in chronic disease management remain systematically underexplored. This review comprehensively analyzes the structural characteristics of brown, red, and green algal polysaccharides, revealing how specific structural features—such as glycosidic linkage patterns and sulfate group positioning—dictate their biological activities. We also demonstrated their multifaceted roles in diabetes, cancer, and cardiovascular diseases through distinct mechanisms, including gut microbiota modulation via short-chain fatty acid production, antioxidant enzyme activation, and targeted inhibition of pathological signaling pathways like mTOR and JAK-STAT3. The work further evaluates extraction methodologies, highlighting the advantages of emerging techniques such as enzyme-assisted and ultrasonic extraction for preserving bioactive integrity. By integrating fundamental research with practical applications in functional foods, this synthesis provides critical insights for harnessing algal polysaccharides in precision nutrition and sustainable biomedicine, while identifying key challenges in standardization and environmental safety that warrant future investigation. Full article

Background/Objectives: The plant species Erophaca baetica (L.) Boiss. (synonym: Astragalus lusitanicus Lam.) is found essentially around the Mediterranean basin, with Morocco as its ancestral territory. The foliage of E. baetica is toxic to small ruminants, and for this reason the plant is often eliminated by farmers, despite its ecological and medicinal potential. The phytochemicals at the origin of the toxicity of E. baetica are not precisely known, but several potentially toxic products have been identified. In particular, aliphatic nitro compounds are present in the aerial parts of the plant, such as 3-nitro-propionic acid (NPA) and its precursor 3-nitro-propanol (NPOH) which are most likely at the origin of the plant toxicity. Results: The present review provides a detailed analysis of the nitrotoxins isolated from E. baetica and their mechanism of action. The covalent targeting of metabolic enzymes such as isocitrate lyase and succinate dehydrogenase by NPA is discussed. The mitochondrial chain blocker NPA is most likely responsible for the brain toxicity of E. baetica, but the presence of other potentially toxic chemicals—such as lusitoxamine and lusitoxamide—is also discussed. Conclusions: This review shed light on the widespread but little-known Mediterranean plant E. baetica and the phytochemicals responsible for the plant’s toxicity. Full article

Background: Ampakines are a family of molecules that enhance the functioning of AMPA-glutamate receptors (AMPAR). High-impact ampakines completely offset receptor desensitization and enhance agonist binding affinity, while low-impact ampakines only modestly affect receptor desensitization and do not alter agonist binding affinity. Nonetheless, little is known about AMPAR recovery following ampakine treatment. Methods: Herein, we study the effects of ampakines on AMPAR recovery and the interaction between high- and low-impact ampakines. Results: The high-impact ampakine CX729 did not induce any current in the absence of glutamate, but it dramatically increased glutamate-induced steady-state inward currents. Recoveries from the enhancement were significantly slower than those for the low-impact ampakine CX516, as was also seen on miniature synaptic currents. Electrophysiological interaction studies suggest that high- and low-impact ampakines may have different binding sites. We further investigated the induction of the potentiated response by measuring glutamate-induced responses after transient applications of CX729 or CX729 plus glutamate. Under both circumstances, subsequent application of glutamate yielded comparably potentiated responses. Furthermore, the recovery time was not different if saline was substituted for glutamate during the recovery period. Conclusions: These observations show that AMPAR potentiation by CX729 does not require the simultaneous presence of glutamate, nor is the slow reversal of the effects of the ampakine altered by subsequent receptor activation. Hence, the slow recovery from the effects of these select ampakines on the AMPAR may be the result of slow dissociation kinetics. We posit that the slow recovery of AMPAR from high-impact ampakines may contribute to the seizurogenic effects of this drug class and that high-impact ampakines that allow for more rapid AMPAR recovery may be safer and more clinically viable candidates. Full article

(1) Background: Mopeia–Lassa reassortant ML29 virus is an investigational, reassortant virus vaccine for the prevention of Lassa fever caused by Lassa virus (LASV). (2) Methods: The vaccine virus ML29-SF was prepared in Vero cells using a serum-free culture medium under Good Manufacturing Practice. A 2-week repeat dose toxicity study was performed in guinea pigs under Good Laboratory Practice (GLP) regulations to assess the local and systemic toxicological effects. (3) Results: Following an intramuscular (IM) or subcutaneous (SC) injection of 10⁴ PFU of ML29-SF LASV vaccine at the start of the study, with a second dose 15 days later, no toxicological response attributable to the vaccine was observed. Vaccine-related effects were not observed in any in-life or post-mortem parameter evaluated, including clinical observations, injection site observations, body temperature, body weight, food consumption, ophthalmology, immunology, hematology, clinical chemistry, gross anatomical pathology, organ weights, and histopathology. An immunogenic response, as measured by the elicitation of IgG antibodies against major LASV immunogens, nucleocapsid and glycoprotein precursor, was observed in all vaccine-treated animals prior to the booster dose (Study Day 15) which endured through the end of the study (Study Day 42). There was no evidence of viral shedding in any vaccinated animal. (4) Conclusions: Overall, this single-dose vaccine was locally and systemically well tolerated even after a two-dose repeat administration, confirming the high level of safety of ML29-SF vaccination and supporting the future evaluation of this LASV vaccine, including in clinical trials. Full article

Background: The GABA_A receptor (GABAAR) potentiator, KRM-II-81, is being developed as a novel antiseizure medication with reduced potential for sedation, tolerance development, and abuse liability. Although KRM-II-81 has been shown to provide antiseizure protection against a broad array of seizure induction paradigms, seizures induced by viral vectors have not been previously studied. GABAARs with specific α subunit compositions have been studied in relation to the reduced side-effect liability of KRM-II-81; however, the role of β subunit composition has yet to be determined. Methods: In the present study, KRM-II-81 was studied against handling-induced seizures in Theiler’s murine encephalomyelitis virus (TMEV)-infected mice. Results: An intracerebral infusion of TMEV on day 0 increased the cumulative seizure burden in mice when assessed for handling-induced seizures on days 3–7. KRM-II-81 (15 mg/kg, p.o., bid) nearly completely suppressed seizures in TMEV-infected mice over the course of daily treatments. The number of the most severe seizures (stage 5, tonic/clonic seizures) in the mice was suppressed to zero by KRM-II-81. Although the selectivity of KRM-II-81 for GABAAR α2/3 receptor subtypes might imbue KRM-II-81 with a reduced side-effect liability, other mechanisms are possible, and the potentiation of β1-containing GABAARs has been implicated in inducing sedation. The role of β subunit composition has yet to be determined for KRM-II-81. In electrophysiological studies with cells transfected with α_xβ₁γ₂ or α_xβ₃γ₂, KRM-II-81 preferentially potentiated GABA responses in cells containing β3 subunits in α2/3-containing GABAARs. Conclusions: The present findings confirm the robust antiseizure activity of KRM-II-81, now extended to a virus-induction model, and suggest a possible role of reduced β1-potentiation in the low side-effect profile of KRM-II-81. Full article

The pharmaceutical industry faces mounting pressure to reduce its environmental impact while maintaining innovation in drug development. Artificial intelligence (AI) has emerged as a transformative tool across healthcare and drug discovery, yet its potential to drive sustainability by improving molecular design remains underexplored. This review critically examines the applications of AI in molecular design that can support in advancing greener pharmaceutical practices across the entire drug life cycle—from design and synthesis to waste management and solvent optimisation. We explore how AI-driven models are being used to personalise dosing, reduce pharmaceutical waste, and design biodegradable drugs with enhanced environmental compatibility. Significant advances have also been made in the predictive modelling of pharmacokinetics, drug–polymer interactions, and polymer biodegradability. AI’s role in the synthesis of active pharmaceutical compounds, including catalysts, enzymes, solvents, and synthesis pathways, is also examined. We highlight recent breakthroughs in protein engineering, biocatalyst stability, and heterogeneous catalyst screening using generative and language models. This review also explores opportunities and limitations in the field. Despite progress, several limitations constrain impact. Many AI models are trained on small or inconsistent datasets or rely on computationally intensive inputs that limit scalability. Moreover, a lack of standardised performance metrics and life cycle assessments prevents the robust evaluation of AI’s true environmental benefits. In particular, the environmental impact of AI-driven molecules and synthesis pathways remains poorly quantified due to limited data on emissions, waste, and energy usage at the compound level. Finally, a summary of challenges and future directions in the field is provided. Full article

Background/Objectives: Dental caries and candidiasis are major health problems worldwide. Dental caries is caused by cariogenic bacteria, especially those belonging to the Streptococcus genus, whereas candidiasis is caused by Candida species. In this study, the antimicrobial activity of a series of synthetic N-methyl-4-piperidone-derived monoketone curcuminoids (MKCs) against Candida albicans, C. krusei, and a representative panel of cariogenic bacteria was assessed. Methods: Fifteen MKCs were synthesized using an environmentally friendly base-catalyzed Claisen–Schmidt condensation between an aromatic aldehyde (R-PhCHO) and N-methyl-4-piperidone ethanol using NaOH as the catalyst. These compounds were evaluated for their antibacterial activity against a representative panel of cariogenic bacteria, along with their antifungal activity against Candida krusei and C. albicans. The antimicrobial activity was determined based on the Minimum Inhibitory Concentration (MIC) values. Results: Most of the compounds were obtained in about 2 h in yields ranging from 40 to 70%. None of the compounds displayed antifungal activity, even at 100 μg/mL, the highest tested concentration. Similarly, none of the compounds were active against Enterococcus faecalis. On the other hand, compounds 1 (R = H), 10 (R = 3,4,5-OMe), and 13 (R = 3-F) displayed moderate activity against Streptococcus mutans (13), S. salivarus (1), L. paracasei (1 and 10), S. mitis (1, 10, and 13), S. sanguinis (1, 10, and 13), and S. sobrinus (13), with MIC values of 250 μg/mL and 500 μg/mL. The presence of the N-methyl-4-piperidone ring was found to boost the antibacterial activity as compared to the corresponding acetone-derived MKCs. Moreover, the antibacterial activity of compounds 10 and 13 was associated with the presence and position of the fluor atom and the methoxy groups at the aromatic ring. Conclusions: This study contributed to a better understanding of the antimicrobial activity of MKCs, whose data in the literature are still scarce. Full article

Background/Objectives: Epilepsy is a common neurological condition characterized by the occurrence of a seizure. It affects around 50 million individuals worldwide, and despite the large quantity of anti-seizure medications available, 30% of epileptic patients still suffer from seizures. Therefore, it is necessary to find new therapeutic options. Interestingly, polydatin has shown promising effects on epilepsy treatment due to its antioxidant and anti-inflammatory properties. Thus, this study aimed to evaluate the effects of polydatin (200, 300, and 400 µM) on a pentylenetetrazol (PTZ)-induced seizure model in wild-type zebrafish (Danio rerio) larvae. Methods: Seizure-like behavior, cell death, reactive species (RS) production, and lipid peroxidation were analyzed. Results: Pre-treatment with polydatin at 200 and 300 µM did not have a significant impact on seizure occurrence and the behavior of animals exposed to PTZ. Diazepam decreased seizure occurrence and increased the latency to achieve each seizure stage. Exposure to PTZ increased the swimming activity, and this effect was suppressed by diazepam but not by polydatin. PTZ exposure increased the RS production, which was significantly attenuated by polydatin at 400 µM and DMSO. Cell death and lipid peroxidation were not changed when compared to the experimental groups. Conclusions: Only the experimental positive control (diazepam) showed anti-seizure effects. Therefore, we failed to observe any anti-seizure effects of polydatin using a zebrafish experimental model. However, we cannot rule out its effects in other experimental models and different treatment protocols. Full article

Background/Objectives: Limitations of conventional treatments for esophageal cancer, which include poor solubility, drug resistance, and undesirable side effects, make it imperative to explore new therapeutic approaches to slow the progression of this disease. This study aims to assess the potential of terpene compounds as anti-cancer agents for esophageal squamous cell carcinoma (ESCC). Methods: This work was carried out following the PRISMA 2020 guidelines to ensure rigorous methodology. Results: A systematic analysis of 34 compounds revealed various mechanisms of action, such as induction of oxidative stress and modulation of apoptotic pathways. The results also show that several compounds, including (1Z,3R,4S,5E,7Z)-1-bromo-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene, dehydrocostus lactone, (3R,4S)-3,4,6,7-tetrachloro-3,7-dimethyl-octene-1-ene, acetyl-macrocalin B, jesridonin, longikaurin A, sphaerococcenol A, DS2, rabdocoestin B, ingenol C, ingenol-3,20-dibenzonate, JDA-202, xerophilusin B, betulinic acid, euphol, and (20S) ginsenoside Rh2, with IC₅₀s below 10 µM, show promising efficacy both in vitro and in vivo, sometimes surpassing certain conventional treatments. Conclusions: However, despite these encouraging prospects, limitations remain, notably a lack of in vivo data and clearly defined mechanisms of action for certain compounds. These challenges require further research to validate their safety and efficacy, facilitating their development as viable therapeutic options for ESCC. Full article