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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access Full Text Article                                                                             Review Article

A Brief Review on Pharmacological Efficacy of Chelidonic Acid

K Harish ¹, S M Sivasankaran ¹, S Manoharan ³* and S M Sakthisankaran ²

¹ Ph.D Research Scholar, Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar-608002, Tamil Nadu, India.

² M.Pharm Student, Department of Pharmacy, Annamalai University, Annamalainagar-608002, Tamil Nadu, India.

³ Professor, Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar-608002, Tamil Nadu, India.

 

 

1. Introduction

Humans have used herbs and natural products for treating various illnesses. Plant-based medicines have been widely used throughout all civilizations due to less toxic effects and affordable at low cost.¹ Phytochemicals are secondary bioactive metabolites found in the plants; that play an important role as an antioxidant, anti-inflammatory, antidiabetic, anticancer and immune-modulatory agents.² Their promising structural and biological properties targeting various genes and proteins make them interesting for drug research and development prospects. ^3,4 

Chelidonium majus is one of the traditional medicinal plants that has been used for various illnesses. Recently, many studies have explored its major bioactive compounds, chelidonine, sanguinarine, berberine and chelidonic acid.^{5, 6} Chelidonic acid a 4-oxopyran-2, 6-dicarboxylic acid is present in various plants such as chelidonium majus⁷, Sorghum vulgare seedlings ⁸, Cassia spectabilis flowers ^9,10 and Gloriosa superba leaves.^{11, 12}  Recently, chelidonic acid has received greater interest due to its diverse pharmacological properties    (Figure 1). It has been reported to possess antioxidant, anti-inflammatory, immunomodulatory, organ protective effects and bone regenerative properties.^{13, 14, 15, 16, 17} 

Oxidative stress plays the major roles in developing many types of diseases including diabetes, cancer, neurodegenerative disorders and cardiovascular problems. The imbalance between the generation of reactive oxygen species and the antioxidant system leads to oxidative stress.¹⁸ Inflammation caused by oxidative stress, can induce pathological processes such as tissue damage, fibrosis and metabolic abnormalities, leading to the development of cancer, diabetes mellitus, neurological diseases and vascular disorders.¹⁹ Chelidonic acid showed strong in vivo antioxidant activity through increasing the production of endogenous antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). ^{15, 20}

Chelidonic acid possesses strong antioxidant and anti-inflammatory properties which will enhance its therapeutic potential (Figure 2).^21,16  It also controls the neurotransmitters implying possible uses in the treatment of depression, ulcerative colitis and atopic dermatitis.^22,23  Furthermore, it mitigates chemotherapy-induced peripheral neuropathy, doxorubicin-induced cardiotoxicity and cisplatin-induced nephrotoxicity by regulating important cellular signaling pathways such as Nrf2, AMPK and NF-κB.^13,14,15

It decreases oxidative stress-induced premature senescence (SIPS) in human skin fibroblast cells, indicating its promising role for anti-aging treatments.²⁴ Chelidonic acid contains calcium complex has been reported to have bone regeneration and tissue engineering properties as it promotes mesenchymal stromal cell differentiation and mineralization.¹⁷ Chelidonic acid has an essential role in hematopoiesis, as revealed in situ and silico models, indicating its promise in regenerative therapy for bone marrow function abnormalities.²⁵ The acute dose toxicity studies demonstrated that there were no toxic effects up to 2000mg/kg b.w and repeated dose toxicity studies also found to be safe.²⁶

This review highlights the biological and pharmacological effects of chelidonic acid reported so far in in vitro and in vivo experimental models.

2. Material and Methods 

The literature search for the therapeutic effects of chelidonic acid was carriedout using various standard citation index platforms such as PubMed, Scopus, Science Direct, Web of Science and Google Scholar, between the years 2010 and 2025. The search terms used for this literature include "Chelidonic acid" and "oxidative stress", "anti-inflammatory effects", "signaling pathways" and "pharmacological effects". The peer-reviewed research publications and reviews were collected with clear mechanisms and standard methodology; however, studies with no mechanistic insights or unclear methodology were removed. This review intends to shed light on chelidonic acid's medicinal potential and future research initiatives.

3. Biological effects of chelidonic acid 

Chelidonic acid has been reported to exhibit various biological activities through numerous in vitro and in vivo models. These activities are attributed by modulate key signaling pathways. Table 1 summarizes the therapeutic efficacies of chelidonic acid reported in various in vitro and in vivo studies.

Acute and repeated dose toxicity study

Acute and repeated dosage toxicity studies are required to assess the safety of phytochemicals before pre-clinical and clinical experiments. Acute studies evaluate the immediate toxic effects and contribute to the lethal dose, whereas repeated dose studies show possible long-term toxicity, target organ damage and safe dosage ranges. These studies are important for better understanding the risk profile, adjusting dose and exceeding regulatory standards for medication development or herbal product approval.²⁷ One of the acute and repeated toxicity study conducted by Khairnar et al., ²⁶ found that chelidonic acid is non-toxic at both dosages.   They follow the OECD guidelines 425 and 407 for acute and repeated dose toxicity studies respectively. For 14 days observation of acute toxicity study, they found that 2000mg/kg b.w of single oral doses of chelidonic acid given to female Wistar rats resulted in no death or apparent evidence of toxicity. During this period rats behavior is normal with no significant differences in body weight, food intake and water consumption compared to control rats. In the repeated dose toxicity study, male and female rats were administered with chelidonic acid 10, 20 and 40 mg/kg/day for 28 days. They found that no significant changes occurred in body weight, hematological parameters (WBC, RBC, hemoglobin and platelets), liver function enzymes (ALT, AST and ALP), renal function parameters (creatinine, urea) and electrolyte levels. Furthermore, the histopathological study revealed that there were no changes in tissue architecture in major organs like the liver, kidney, brain and heart. Additionally, organ weights in all treated animals were shown more similar to those animals not treated with chelidonic acid. 

 Neuroprotective effects of chelidonic Acid

Currently, there are no anticancer drugs that have both minimal side effects and therapeutic potential especially, in patients treated with taxanes such as paclitaxel. Paclitaxel's major challenge is potential neurotoxicity that leads to poor outcomes for patients' health.²⁸ Khairnar et al.,¹⁵ demonstrated that chelidonic acid protects against chemotherapy-induced neuropathy in Wister rats.  Chelidonic acid given orally at dosages of 10, 20 and 40 mg/kg for 21 days, coupled with paclitaxel injections reduced neuropathy. The administration of chelidonic acid significantly reduces neuropathic pain such as mechanical allodynia, hyperalgesia and thermal hyperalgesia, as assessed by the Von Frey, tail immersion, hot plate and Randall-Selitto tests. These observations concluded chelidonic acid restored the normal sensory responses in peripheral neuropathy. Chelidonic acid protects the neurons by showing antioxidants and anti-inflammatory effects. It decreased the malondialdehyde (MDA) and enhanced the activity of key endogenous antioxidant enzymes including SOD, catalase and glutathione (GSH). Furthermore, it enhanced the Nrf2 signaling pathway, which improved cellular defenses against ROS. Chelidonic acid's anti-inflammatory inhibited reduce the production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β. It also activated AMPK phosphorylation for energy balance and downregulated HIF-1α to decrease the hypoxia-induced injury in peripheral neurons. These activities reduced the paclitaxel-induced peripheral neuropathy. In addition, histopathological evidence supported its neuroprotective effects. Chelidonic acid substantially reduced axonal degeneration, myelin sheath degradation and leukocyte infiltration in paclitaxel-treated rats' sciatic nerve tissues.  This tissue preservation effect is critical for sustaining nerve conduction velocities, as demonstrated by improvements in both motor and sensory nerve conduction velocities (MNCV and SNCV) in chorionic acid-treated mice. 

 Cardioprotective effects of chelidonic acid 

Doxorubicin, one of the anticancer drugs that is primarily used to treat breast, ovarian and other types of malignancies. The significant side effect of doxorubicin is cardiotoxicity.²⁹ Nowadays many studies suggested that phytochemical reduces the side effects of many anticancer drugs.³⁰ Khairnar et al., ¹³ suggested that chelidonic acid has cardioprotective effects against doxorubicin (DOX)-induced cardiotoxicity in male Wistar rats. Doxorubicin induces oxidative stress, inflammation and mitochondrial dysfunction. Chelidonic acid oral administration significantly reduced DOX-induced heart damage. This study confirmed that chelidonic acid enhanced the ST-segment elevation, QT interval shortening and QRS complex length normalization. These signals are indicators of the protection of cardiac electrical activity and decreased arrhythmia risk. Chelidonic acid also reduced oxidative stress by lowering malondialdehyde (MDA) levels and restored antioxidant defenses (SOD, CAT and GSH), possibly through Nrf2 signaling activation. The serum cardiac damaged markers such as CK-MB (Creatine Kinase-MB Isoenzyme), LDH (Lactate Dehydrogenase), AST (Aspartate Aminotransferase) and cTn-T (Cardiac Troponin-T) were dramatically decreased, demonstrating CA's cardioprotective properties. Chelidonic acid reduced the levels of TNF-α, IL-6 and CRP, probably through NF-κB suppression, avoiding cardiac tissue damage and fibrosis. Furthermore, histopathological examinations revealed that chelidonic acid maintains normal cardiomyocyte structure, reduced fibrosis and decreased myocardial necrosis. Chelidonic acid increased the levels of LVEDP and contraction/ relaxation rates (+dp/dt and -dp/dt). These findings strongly suggested that chelidonic acid could reduce DOX-induced cardiotoxicity via antioxidant, anti-inflammatory and cardiac function-signaling pathways.

Nephroprotective effect of chelidonic acid

Cisplatin, a known chemotherapy drug, is known to cause kidney damage.³¹ Some studies indicated that some phytochemicals can provide nephroprotection (Tienda-Vázquez et al.,).³²  Khairnar et al.,¹⁴ reported that chelidonic acid 10, 20 and 40 mg/kg b.w for four weeks of oral administration provide significant protection against the cisplatin-induced nephrotoxicity, as evidenced by improvements in kidney function indices such as serum albumin and creatinine levels. Cisplatin was given intraperitoneally (i.p.) at a dosage of 5 mg/kg once a week for 4 weeks to cause nephrotoxicity. Chelidonic acid mitigates the production of pro-inflammatory cytokines such as TNF-α, IL-6 and TGF-β and increased the production of nuclear factor erythroid 2-related factor 2 (Nrf2). Chelidonic acid treatment significantly increased phospho-AMPK and hypoxia-inducible factor 1-alpha (HIF-1α) levels, which are important in stress responses, energy control and survival. Histopathological staining revealed chelidonic acid reduced kidney damage while increasing tissue preservation and regeneration. These cumulative results suggested that chelidonic acid has the potential therapeutic adjuvant to cisplatin, enhancing its safety profile and raising its clinical applications in cancer treatment.

 

 

Effect of chelidonic acid against atopic dermatitis

Eczema (atopic dermatitis) is a skin condition that causes skin barrier malfunction because of genetics, immune system abnormalities and environmental stimuli. Several clinical investigations have demonstrated the therapeutic benefit of herbal extracts in treating eczema. As a result, investigating phytochemicals that might suppress IgE and cytokines, in particular, IL-4, a major contributor to IgE hyperproduction, holds promise for possible therapies.³³ Kim et al., ³⁴ reported that chelidonic acid mitigated the symptoms of apoptotic dermatitis (AD) through its anti-inflammatory effects. In 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model, chelidonic acid improved hallmark symptoms such as eczema, erythema and skin dryness, while also significantly lowering serum histamine and immunoglobulin E (IgE) levels by 28.93% and 36.21%, respectively. These findings emphasize the role of chelidonic acid in addressing critical features of AD pathology, including immune dysregulation and skin inflammation. Chelidonic acid suppressed the expression of key inflammatory mediators, such as TNF-α, IL-6, COX-2 and iNOS, in DNCB-induced AD-like skin lesions and LPS-stimulated mouse peritoneal macrophages. The suppression of these inflammatory cytokines and enzymes was dose-dependent, indicating CA's ability to control the inflammatory response. The study found that chelidonic acid dramatically decreased the nuclear translocation of NF-κB, a key transcription factor in inflammatory signaling pathways. Chelidonic acid inhibited NF-κB activation at a rate of 42.05% in AD-like skin lesions and 37.17% in macrophages, indicating that it targets NF-κB signaling to reduce inflammation. The study emphasizes the potential of chelidonic acid as a therapeutic agent for Alzheimer's disease, offering a safer alternative to traditional steroid therapies that are linked with long-term negative effects. Chelidonic acid is a potential method for controlling Alzheimer's disease since it addresses basic pathological aspects such as pruritus, immunological dysregulation and chronic inflammation. However, further research is required to investigate its long-term safety, effectiveness and precise molecular processes in clinical settings.

Effect of chelidonic acid oxidative stress-induced premature cellular senescence 

Aging is a complex biological process characterized by decreased physiological function and an increased risk of chronic illness. Oxidative stress, caused by ROS buildup, is a major cause of aging because it damages DNA, proteins and lipids, resulting in cellular senescence.³⁵ Phytochemicals are thought to counteract oxidative stress, lower ROS levels, postpone senescence and enhance tissue regeneration. They reduce senescence-associated β-galactosidase (SA-βgal) activity, a hallmark of cellular aging, providing natural protection from age-related illnesses.³⁶ Turkoglu et al.,²⁴ reported that chelidonic acid considerably inhibited oxidative stress (200-µM hydrogen peroxide) induced premature cellular senescence in human fibroblast cells. Chelidonic acid’s 250µM and 500µM treatment dramatically reduced the SA-βgal activity by 27.76% and 51.57%, respectively. Chelidonic acid improved the nuclear morphology and DNA damage determined by DAPI staining, AOEt/Br staining and comet assay. Due to its antioxidant activity, it provides senomorphic effects by reducing the intracellular ROS levels and lipid peroxidation levels while increasing the SOD and reducing glutathione peroxide activity. The in silico studies suggested that chelidonic acid binds strongly to senescence-associated proteins such as p16, p21 and p53 with great affinity. It may regulate the expression of critical senescence-related genes and proteins such as p21, p16 and pRB1, underlining its involvement in regulating the p53-p21 and p16-pRB1 pathways. This study found that chelidonic acid has both senomorphic and senolytic properties and it may thus be used for treating oxidative stress-induced cellular aging and age-related illnesses.  

Antidepressant-like effects of chelidonic acid

Depression is one of the most prevalent psychiatric diseases and its high incidence and death rates result in a major disease burden. Contemporary therapies for depression include a variety of synthetic medicines, which have drawbacks such as side effects, single targets and slow onset of action. Unlike synthetic drugs, phytochemicals provide a multi-target and multi-pathway approach to depression treatment.³⁷ Jeong et al., ²² reported that chelidonic acid exerted antidepressant effects through the regulation of neurotransmitters and inflammatory pathways in mice. Chelidonic acid dose-dependently reduced the immobility time in the forced swimming test, a behavioral model for testing antidepressant medications. In addition, locomotor activity was determined using the open field test (OFT), which confirmed that chelidonic acid did not cause hyperactivity or anxiety-like behavior, suggesting its specificity in targeting depression-related pathways. Chelidonic acid promotes hippocampal neurogenesis by increasing the number of Nissl bodies in the dentate gyrus area of the hippocampus. This compound also regulated the neuroprotection, synaptogenesis and mood control pathways by increased brain-derived neurotrophic factor (BDNF) production and Extracellular Signal-Regulated Kinase (ERK) phosphorylation. Chelidonic acid regulated emotional and cognitive function by increasing the hippocampal monoamine neurotransmitters such as serotonin (5-HT), dopamine and norepinephrine. This study also showed that chelidonic acid considerably decreased the neuroinflammation in the hippocampus by decreasing the levels of IL-1β, IL-6 and TNF-α. Chelidonic acid appears to be a good option for developing alternative antidepressant treatments.

Anti-ulcerative colitis effect of chelidonic acid   

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by recurrent gastrointestinal pain and bloody diarrhea, which increases the risk of colorectal cancer. Despite advances in therapy, UC remains incurable and current medications frequently result in severe side effects. Researchers continue their search for safer and more effective medications for UC.³⁸ Recent research suggested that plant-derived substances with anti-inflammatory and antioxidant characteristics are intriguing solutions for UC therapy. These compounds, when used together with microbiota-targeted approaches, provide new promise for restoring gut balance and relieving symptoms.^39,44 Kim et al.,²³ suggested that chelidonic acid possesses strong anti-ulcerative colitis activity through its anti-inflammatory properties in dextran sulfate sodium (DSS) induced ulcerative colitis in female BALB/c mice. DSS alone caused substantial clinical symptoms such as weight loss, diarrhea, rectal bleeding and colon shortening. Chelidonic acid orally at a dosage of 20 mg/kg/day over 7 days of administration significantly reduced these symptoms. Chelidonic acid treatment also reduced the levels of inflammatory mediators in both serum and colonic tissues, such as IL-6 and TNF-α confirmed by enzyme-linked immunosorbent test (ELISA). Chelidonic acid reduced the upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) confirmed by Western blot analysis. The study found that chelidonic acid inhibited hypoxia-inducible factor-1 alpha (HIF-1α), which is linked to inflammatory reactions in ulcerative colitis. These findings strongly demonstrated that chelidonic acid has the potential to treat ulcerative colitis by regulating of production of inflammatory mediators and minimizing mucosal damage. In this study, chelidonic acid effects on ulcerative colitis are comparable to sulfasalazine, a widely used ulcerative colitis drug. This study strongly suggested that chelidonic acid can serve as an alternate therapeutic for the treatments of UC and other bowel disorders. 

Anti-inflammatory effect of chelidonic acid 

Asthma, allergic rhinitis and rheumatoid arthritis are chronic inflammatory diseases characterized by immune dysregulation and elevated levels of pro-inflammatory cytokines such as IL-6. Mast cells play a key role in the pathogenesis of these conditions by releasing inflammatory mediators upon activation. ^{40, 41, 42} Sin et al. ⁴³ demonstrated that chelidonic acid treatment dose-dependently reduced the level of IL-6 production in PMACI-stimulated HMC-1 cells. It prevents IκBα degradation, inhibiting NF-κB activation and suppressed caspase-1 activation. These findings suggested that chelidonic acid as a potential therapeutic for mast cell-related inflammatory diseases like asthma, allergic rhinitis and rheumatoid arthritis.        

Anti-allergic effects of chelidonic acid

Oh et al., ²¹ reported that chelidonic acid has anti-allergic effects in an ovalbumin-induced allergic rhinitis mouse model. They discovered that chelidonic acid treatments significantly reduced the nose and ear rubbing activity, which is a clinical indication of allergic rhinitis. Chelidonic acid decreased the levels of IgE and histamine release in the blood; these are the critical indicator of allergic response. Chelidonic acid increased the IFN-γ (Th1 cytokine) levels while reducing the IL-4 (Th2 cytokine) levels, these effects are indicating a change from a Th2-dominated allergic reaction to a Th1 response.  Furthermore, chelidonic acid reduced the production of IL-1β and COX-2 in nasal mucosa tissues. The histological study revealed that chelidonic acid treatments reduced eosinophils and mast infiltration. The study also found that chelidonic acid inhibited the caspase-1 activity, which activated IL-1β in nasal tissues and human mast cell lines (HMC-1). They suggested that chelidonic acid has anti-inflammatory effects by the regulation of inflammasome activation and the caspase-1 pathway. In conclusion, chelidonic acid controls the Th1/Th2 balance and reduces the inflammatory cytokines, mitigating the eosinophil and mast cell infiltration and suppressing the caspase-1/IL-1β axis.   

4. Conclusion

Chelidonic acid has great therapeutic potential due to its promising endogenous antioxidant, anti-inflammatory and immunomodulatory effects. Existing experimental evidence, notably from animal research suggests its potential for treating various diseases. However, the interaction of chelidonic acid with critical signaling pathways is still poorly known, requiring extensive investigations to reveal its role in wide molecular processes. Future preclinical studies are required to determine the dose-response relationship, long-term safety profile and pharmacokinetic features of chelidonic acid, which will eventually help reveals its full therapeutic potential in disease management and medication development. The discovery of chelidonic acid as a potential therapeutic agent might open the way for natural medication formulations to treat cancer, diabetes mellitus, cardiovascular disease, neurological disorders.

 

 

 

Figure 1: Biological effects of Chelidonic Acid

 

Figure 2: Mechanistic flowchart of antioxidant and anti-inflammatory effects of chelidonic acid

 

 

Table 1:   Summarizes the therapeutic potential of chelidonic acid 

 

 

Conflict of Interest: The authors declare no potential conflict of interest concerning the contents, authorship, and/or publication of this article.

Funding: The authors declared that this study has received no financial support.

Informed Consent Statement: Not applicable. 

Data Availability Statement: The data supporting this paper are available in the cited references. 

Ethical approval: Not applicable.

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