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    Review

    Nephroprotective Role of Boerhavia diffusa: A Mechanistic Review of Gene Expression and Signaling Cascades

    Dinesh Kumar Robert1,3, Laksmanan Govindan1★, Kalpana Ramachandran2, Senthilkumar Sivanesan1, Kanimozhi Selvakumaran3, Sathish Adithya Rajadhinakaran4★ Corresponding author

    1. 1Department of Research and Development, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, INDIA.
    2. 2Department of Anatomy, Sri Ramachandra Institute of Higher Education, Chennai, Tamil Nadu, INDIA.
    3. 3Department of Anatomy, Sri Muthukumaran Medical College Hospital and Research Institute, Chennai, Tamil Nadu, INDIA.
    4. 4Department of Nanju Maruthuvam, National Institute of Siddha, Research institution in Chennai, Tamil Nadu, INDIA.

    CORRESPONDENCE

    Laksmanan Govindan

    Department of Anatomy, Saveetha Institute of Medical and Technical Sciences, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, INDIA.

    lakshmanang261988@gmail.com

    ORCID: 0000-0002-7503-354X

    Received: 07-01-2026; Revised: 27-04-2026; Accepted: 18-06-2026.

    Volume 18, Issue 4 · pp. 1187–1194 · PUBLISHED Jul-Sep 2026 · DOI: 10.5530/pres.20260077

    ABSTRACT

    Drug induced nephrotoxicity is a major clinical challenge, arising from diverse therapeutic agents such as cisplatin, aminoglycosides, streptozotocin, NSAIDs, antivirals, methotrexate, calcineurin inhibitors, and radiocontrast media. These agents damage renal tissue through overlapping mechanisms including oxidative stress, mitochondrial dysfunction, apoptosis, inflammation, and fibrosis, leading to acute kidney injury and progression to chronic kidney disease. Conventional mitigation strategies remain limited, prompting growing interest in plantderived secondary metabolites with multitargeted protective effects. Boerhavia diffusa Linn. (Punarnava), a traditional herb, has demonstrated nephroprotective potential through its diverse phytoconstituents such as boeravinones, punarnavine, flavonoids, saponins, and phenolic acids. These compounds modulate key signaling pathways including Nuclear Factor Erythroid 2Related Factor 2/ Antioxidant Response Elements (Nrf2/ARE), Nuclear Factor Kappa B (NFκB), MitogenActivated Protein Kinase, Phosphoinositide 3Kinase/ Protein Kinase B (MAPK, PI3K/Akt), and Transforming Growth Factor Beta (TGFβ/Smad), thereby attenuating oxidative damage, suppressing inflammation, regulating apoptosis, and reducing fibrosis. This review synthesizes mechanistic insights into druginduced nephrotoxicity and highlights the translational relevance of B. diffusa as a multitarget nephroprotective agent.

    KEYWORDS

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    FULL TEXT

    INTRODUCTION

    Druginduced nephrotoxicity remains a main clinical problem, because, kidney is highly susceptible to xenobiotic injury having its role in drug metabolism and excretion. Renal damage is commonly caused by therapeutic drugs such as cisplatin, aminoglycosides, streptozotocin, NSAIDs, antivirals, methotrexate, calcineurin inhibitors, and radiocontrast agents, through diverse mechanisms such as oxidative stress, mitochondrial dysfunction, apoptosis of Renal tissue, inflammation of tubules, crystal deposition, and fibrosis of the renal parenchyma (Pabla et al., 2008; Manohar et al., 2018; Gumbar et al., 2023; Li et al., 2024; Pansare et al., 2025; Khatlan et al., 2024). All these clinical conditions are manifested as Acute Renal failure, proteinuria, electrolyte imbalances, leading to Chronic Kidney Disease (CKD), frequently resulting in treatment complications and finally limit the usage of drugs (Ahsan et al., 2025; Rodríguez-Novoa et al., 2010; Widemann et al., 2006).

    Therefore, it is crucial to mitigate nephrotoxicity in order to maintain renal function and to guarantee safe and efficient medication. Partial protection is offered by traditional methods like dose modification and hydration, although natural compounds and secondary metabolites with anti-inflammatory, anti-fibrotic, and antioxidant qualities are receiving more attention (Howard et al., 2016, Nageh et al., 2025, Persson et al., 2005). Plant-derived drugs have demonstrated potential in reversing drug-induced kidney impairment by altering important signaling pathways, such as Nrf2/ARE, NF κB, MAPK, PI3K/Akt, and TGF β/Smad (Cho et al., 2022; Patel et al., 2024).

    Among these, the popular Ayurvedic medicinal herb B. diffusa Linn. (Punarnava) (Figure 2) has become a powerful nephroprotective agent (Kaur, 2019). The phytoconstituents boerhavinones, punarnavine, flavonoids, and saponins present in B. diffusa Linn. Scavenge free radicals, reduce inflammatory mediators, modulate apoptosis, and attenuate fibrosis to provide protective benefits (Varsha et al., 2025; Oseni et al., 2024; Patel et al., 2025; Nayak et al., 2016; Yadav et al., 2024). Since it enables the logical incorporation of phytochemicals into nephroprotective methods and offers translational insights for clinical application, an understanding of these pathways is essential. Thus, the purpose of this review is to build a framework connecting pharmacological impairment with phytochemical intervention, define the molecular basis of drug-induced nephrotoxicity, and emphasize the protective role of B. diffusa and its secondary metabolites. This study aims to increase awareness on Punarnava's function in reducing kidney damage and guiding the development of new treatments by integrating mechanistic toxicology and ethnopharmacology.

    METHODOLOGY

    The extensive literature search was carried out in the largest scientific databases such as PubMed, Scopus, Web of Science, and Google Scholar. The keywords used to search included the combinations of the following terms: Boerhavia diffusa, Punarnava, nephrotoxicity, nephroprotection, oxidative stress, Nrf2/ARE, NF-kB, MAPK, PI3K/Akt, and TGF-b/Smad. The inclusion criteria were limited to peer-reviewed research that examined the molecular pathways of the drug-induced kidney injury and the nephroprotective properties of the plant-based phytochemicals. To combine the traditional knowledge with the evidence of modern mechanisms, ethnopharmacological surveys as well as analytical studies on Boerhavia diffusa were also taken into account.

    REVIEW OF LITERATURE

    Phytochemistry of Punarnava

    In Ayurveda and ethnomedicine, Boerhavia diffusa Linn. is a well-known medicinal plant with a variety of therapeutic uses, especially for renal conditions (Wudali et al., 2020). Modern analytical methods like GC-MS and thorough phytochemical profiling, which uncover a wide range of bioactive ingredients, have validated its phytochemical richness (Juneja et al., 202).

    B. diffusa leaf extract was found to contain flavonoids and alkaloids, particularly punarnavine, a quinolizidine alkaloid. According to qualitative and quantitative GC-MS analysis (Saraswati et al., 2013; Rai et al., 2024), phenolic acids, terpenoids, sterols, saponins, and other secondary metabolites are present in various extracts of B. diffusa that add to its therapeutic value, as well as rotenoids/lignans, specifically boeravinones A-H (Chaudhary et al., 2011, Wang et al., 2023; Bhattarai et al., 2024; Kumar et al., 2025) (Table 1). Ethnomedicinal surveys among indigenous communities in the Indian subcontinent further highlight the plant’s traditional use in kidney ailments, edema, and inflammatory conditions, attributing these effects to its phytochemical diversity (Pandey, 2025; Ahmed et al., 2024). These compounds are mechanistically linked to antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic activities (Gaur, 2022; Santhosh et al., 2023).

    Table 1: Phytochemical Classes and Mechanistic Roles of Boerhavia diffusa Constituents in Nephroprotection.
    ClassRepresentative CompoundsPlant Part / ExtractAnalytical MethodMechanistic / Therapeutic Relevance
    AlkaloidsPunarnavineRoot, leafPhytochemical screening, FTIRAnti-inflammatory, immunomodulatory, nephroprotective
    Rotenoids / LignansBoeravinones A-HRootGC-MS, LC-MSAntioxidant, anti-apoptotic, anti-fibrotic
    FlavonoidsQuercetin, kaempferol derivativesLeafGC-MS, FTIRROS scavenging, cytoprotection
    Phenolic acidsCaffeic acid, hydroxycinnamatesLeafGC-MSNrf2 activation, antioxidant defense
    SaponinsSteroidal saponinsWhole plantPhytochemical screeningAnti-fibrotic (↓ TGFβ/Smad), immunomodulatory
    Terpenoids and SterolsStigmasterol, β-sitosterolLeafGC-MSAnti-inflammatory, membrane stabilizing
    Lipids and Fatty acidsPalmitic acid, linoleic acidLeafGC-MSEnergy metabolism, membrane roles
    Carbohydrates and GlycoproteinsPolysaccharides, glycoprotein fractionsWhole plantPhytochemical screeningSupportive metabolic and immunomodulatory roles
    ProteinsBioactive protein fractionsWhole plantPhytochemical screeningStructural and enzymatic roles
    Other metabolitesAmino acids, sugarsLeaf/rootPhytochemical screeningSupportive metabolic roles

    Drug Induced Nephrotoxicity

    Diverse substances that cause renal damage through overlapping mechanisms can lead to drug-induced nephrotoxicity. Here, a few mechanisms have been described (Figure 1). Cisplatin, a popular chemotherapeutic medicine (Figure 3), disrupts the functions of the endoplasmic reticulum and mitochondria and causes oxidative stress damaging proximal convoluted tubules. This causes DNA adhesion formation, reactive oxygen species generation, inflammatory cytokine release, and renal tubule necrosis, which can result in Acute Kidney Injury (AKI) or chronic kidney injury (Miller et al., 2010; Tang et al., 2023). Gentamicin, an aminoglycoside on accumulation in lysosomes of renal tissue causes Tubular necrosis and ultimately renal impairment, which activates phospholipids and produces reactive oxygen species (Gumbar et al., 2023). Streptozotocin, a chemotherapeutic agent commonly used in research to induce diabetes in rats, causes glomerular damage through oxidative stress and advanced glycation end products resulting from hyperglycemia, ultimately leading to diabetic nephropathy (Li et al., 2024; Pansare et al., 2025). Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) reduce prostaglandin synthesis, lower renal blood flow, and heighten the likelihood of ischemic injury, which can lead to necrosis of the renal papilla (Ahsan et al., 2025). Antivirals such as tenofovir and acyclovir are associated with mitochondrial toxicity and crystal nephropathy, manifesting as obstructive tubular injury and chronic dysfunction (Rodríguez-Novoa et al., 2010). Methotrexate, particularly at high doses, can precipitate within renal tubules causing crystal nephropathy and direct tubular toxicity, which delays drug clearance and leads to systemic toxicity (Howard et al., 2016). Calcineurin inhibitors (cyclosporine, tacrolimus) induce vasoconstriction, endothelial dysfunction, and interstitial fibrosis, contributing to chronic nephrotoxicity (Nageh et al., 2025). Radiocontrast agents precipitate acute tubular injury through oxidative stress, vasoconstriction, and TLR4/MyD88mediated inflammation (Cho et al., 2022).

    Figure 1: Mechanism of Nephrotoxicity.
    Figure 2: Image of the plant B. diffusa.
    Figure 3: Drug induced Nephrotoxicity.

    Antiviral medications like tenofovir and acyclovir are associated with mitochondrial toxicity and crystal nephropathy, manifesting as obstructive tubular injury and chronic dysfunction. Methotrexate, particularly in higher doses, can precipitate within renal tubules, causing crystal nephropathy and direct toxicity to the tubules, which hinders drug clearance and results in systemic toxicity. Calcineurin inhibitors lead to vasoconstriction, endothelial dysfunction, and interstitial fibrosis, all of which contribute to chronic nephrotoxicity. Radiocontrast agents can cause acute tubular injury.

    Mechanisms of Nephroprotection

    Nrf2/ARE signaling in Nephroprotection

    Nrf2 inhibit lipid peroxidation and regain the antioxidant enzyme activity in gentamicin induced renal failure proved to recover the activity of SOD and catalase (Das et al., 2023) (Figure 1). Nrf2 is a transcription factor that is usually bound by Keap1 at the cytoplasm, which facilitates its ubiquitination and degradation by proteasomes (Lin et al., 2023). On the exposure of phytochemicals or oxidative stress Nrf2 dissociates with Keap1 and translocates to the nucleus (Nezu et al., 2020). Nrf2 binding to Antioxidant Response Elements (AREs) and activating HO 1 and NQO1 genes is found in the nucleus (Guerrero-Hue et al., 2020; Hafez et al., 2019). This signaling pathway improves antioxidants, decreases ROS and prevents oxidative damage in renal tissue (Molaei et al., 2021).

    Activators of Nrf2 have been well established to be natural products such as flavonoids and phenolic acids (Mohan et al., 2020). Phytochemicals stimulating the Nrf2 signaling pathway with subsequent HO 1 and NQO1 upregulation have been reported in B. diffusa, including quercetin derivatives, caffeic acid, and boeravinones (Santhosha et al., 2021).

    NFκB signaling in Nephroprotection

    NFκB is a transcription factor which is normally held in the cytoplasm by inhibitory proteins (IkBs), inhibiting its nuclear activity (White et al., 2020). IkB is phosphorylated, degraded upon stress signal stimulation (via ROS, cytokines or by TOLL-like receptors) and NFκB (p65/p50) translocate into the nucleus (Na et al., 2024). NFκB also binds to kB response elements in the nucleus and transcription of pro-inflammatory mediators such as TNFα, IL-6, COX-2, and adhesion molecules (Altindag, 2022). This signaling cascade intensifies inflammation, directly stimulates renal fibrosis, and increases the speed of nephrotoxic damage

    Natural substances, like umbelliferone, sulbutiamine, silymarin, kaempferol, and berberine, have been found to inhibit the action of NFκB, thus decreasing the release of cytokines and preserving renal tissue (Ali et al., 2021; Ghaiad et al., 2023; Alshehri et al., 2022; Zhu et al., 2018). There are claims of phytochemicals in Boerhavia diffusa like punarnavine, boeravinones, flavonoids and saponins to inhibit NF kB signaling resulting in reduced TNFα and IL-6 expression. These substances inhibit inflammatory processes and recover renal activity in models of cisplatin and gentamicin induced nephrotoxicity.

    MAPK signaling in Nephroprotection

    The Mitogen-Activated Protein Kinase (MAPK) signaling pathway is a key regulator of cellular stress responses that mediate inflammation, apoptosis and fibrosis in chronic kidney disease. MAPKs, including p38, JNK, and ERK, are activated in response to oxidative stress and nephrotoxic insults, which results in the activation of pro-inflammatory cytokines and pro- apoptotic genes transcription (Zhang et al., 2018; Jiang et al., 2020). This signaling cascade is involved in tubular damage, glomerulosclerosis and diabetic and toxic nephropathy progression.

    Natural antioxidants have been found to regulate the MAPK activity and thus safeguard the renal tissue. As an example, Fangchinoline mitigates the effect of diabetic nephropathy by inhibiting the MAPK signaling pathways and renal inflammation. Salvianolic acid A prevents kidney disease in nephrectomized rats with 5/6 kidneys and suppresses NFκB and p38 MAPK intricate. Mangiferin prevents cisplatin-induced acute kidney injury by regulating MAPK signaling, inhibiting apoptosis and oxidative stress (Sahu et al., 2019). Correspondingly, an isoflavone dietary antioxidant called daidzein reduces oxidative, apoptotic, and inflammatory response of cisplatin-induced nephrotoxicity by regulating the MAPK pathway (Tomar et al., 2020).

    PI3K/Akt Signaling in Nephroprotection

    The phosphoinositide 3kinase PI3K/Akt signaling is one of the main regulators of cell survival, metabolic response and stress in renal tissue. The PI3K, on activation, phosphorylates Akt, which then regulates downstream targets, including mTOR and GSK3b, facilitating anti apoptotic signaling and cellular resilience (Liu et al., 2015). The dysregulation of this pathway can also be found to cause apoptosis, inflammation, and nephrotoxicity progression in ischemic and diabetic models (Hasan et al., 2020).

    Natural compounds have also shown nephroprotective effect by the regulation of PI3K/Akt signaling. Activation of PI3K/Akt during ischemia/reperfusion injury suppressed oxidative stress and apoptosis, and polydatin inhibited these phenomena. Extracts of Celastrus paniculatus attenuate the lead acetate induced nephrotoxicity through PI3K/Akt activation, which regains the renal architecture and function (Balaji et al., 2021). Phillygenin enhances diabetic nephropathy by suppressing inflammatory diseases and apoptosis by regulating TLR4/MyD88/ NFκB and PI3K/Akt/ GSK3β-signaling (Feng et al., 2025). Quercetin also protects the kidneys during ischemia/reperfusion injury through the Akt/mTOR axis and consequently the apoptosis and oxidative injury. Likewise, andrographolide is a multi-target therapeutic agent that has a protective effect on diabetic nephropathy and its mechanism is mediated by changes in the pathways of STAT3 and PI3K/Akt (Yin et al., 2025).

    TGFβ/Smad Signaling in Nephroprotection

    A key mediator of renal fibrosis and Epithelial to Mesenchymal Transition (EMT) is the transforming growth factor β) TGFβ/Smad pathway. When activated, the TGF β attaches to receptors and the Smad2/3 are phosphorylated and translocate to the nucleus and activate the transcription of pro fibrotic genes including collagen and fibronectin. This signaling pathway facilitates extracellular matrix, tubular atrophy and transition of acute kidney injury to chronic kidney disease (Zou et al., 2025).

    Attack on TGF β /Smad signaling has proven to alleviate the effects of fibrosis and to recover renal function. Azilsartan improves nephroprotective properties of adipose tissue derived mesenchymal stem cells (AT-MSCs) against cisplatin triggered EMT by inhibiting oxidative stress and preventing TGF β /Smad stimulation at the same time. Rhubarb prevents tubulointerstitial fibrosis in chronic kidney disease by suppressing TGF β /Smad signaling and restoring abnormal metabolomic changes (Fawzy et al., 2023). Chrysophanol also alleviates interstitial fibrosis in the kidney by inhibiting the TGF β /Smad pathway, which diminishes the collagen accumulation and scarring of tissues (Zhang et al., 2018).

    Suppression of Caspase Mediated Apoptosis in Nephrotoxicity

    Apoptosis is a highly controlled form of cellular homeostasis, which may cause tubular cell death and nephrotoxicity progression when over-activated in the renal tissue. Mitochondrial dysfunction and caspase-9 activation are caused by the intrinsic pathway, which is mediated by cytochrome c release, whereas death receptor signaling and caspase-8 activation are caused by the extrinsic one. Both of them converge to caspase-3, which leads to fragmentation of DNA and programmed cell death (Zou et al., 2025).

    The Bcl-2/Bax ratio is a determining factor of mitochondrial integrity. Anti apoptotic Bcl 2 stabilizes the mitochondrial membrane and inhibits the release of cytochrome c, but pro apoptotic Bax facilitates the mitochondrial outer Membrane Permeabilization (MOMP) and apoptosis. There are also changes of Bax dominance in nephrotoxic model which results in mitochondrial dysfunction and tubular injury (Palabiyik AA, 2025; Saddam et al., 2024).

    Pharmacological agents and natural compounds have been demonstrated to reduce the apoptosis in models of kidney injury. Azilsartan increases the nephroprotective ability of Adipose Tissue derived Mesenchymal Stem Cells (AT-MSCs) in cisplatin induced EMT by decreasing oxidative stress and inhibiting apoptotic process via regulating TGFβ /Smad signaling. Rhubarb prevents tubulointerstitial fibrosis in chronic kidney disease by inhibiting apoptosis in addition to suppressing TGFβ /Smad signaling (Zhang et al., 2018). Chrysophanol suppresses renal interstitial fibrosis by attenuating pro apoptotic genes and by preventing Smad-dependent transcription (Dou et al., 2020).

    Phytochemicals including boeravinones, punarnavine and quercetin analogs have been suggested to elevate Bcl-2 and decrease Bax in B. diffusa to preserve mitochondrial integrity and minimize caspase 3 activation (Mayurya et al., 2023).

    TLR4/MyD88/NFκB Signaling in Nephroprotection

    Toll like receptor 4 (TLR4)/MyD88/ NFκB pathway is a mediator of innate immune responses in the kidney. When TLR4 is triggered by danger signals (lipopolysaccharide, contrast agents or oxidative stress), MyD88, an adaptor protein, targets the TLR4 and triggers downstream phosphorylation cascades leading to the activation of NFκB. This triggers the pro inflammatory cytokines such as TNFα, IL-1 β and IL-6 transcription, and worsens renal inflammation and is one of the causes of tubular injury and fibrosis (Wang et al., 2020; Yue et al., 2017).

    Kidney injury inhibited with the help of natural compounds and pharmacological agents was demonstrated to affect this pathway. Indicatively, Phillygenin enhances diabetic nephropathy by suppressing inflammatory and apoptotic processes by modulating TLR4/MyD88/ NFκB and PI3K/Akt/GSK3 β signaling. Atorvastatin decreases contrast induced acute kidney injury by inhibiting TLR4/MyD88 signaling, which inhibits the release of cytokines and oxidative stress (Yue et al., 2017). Inflammatory kidney injury induced by lipopolysaccharide is prevented by Dioscin through the microRNA let-7i/TLR4/MyD88 pathway, which revealed the involvement of microRNA regulation in nephroprotection (Qi et al., 2016).

    Other phytochemicals including boeravinones and punarnavine have been reported to inhibit TLR4/MyD88/NF signaling in B. diffusa, which suppresses the expression of pro inflammatory cytokines and has been shown to improve renal function in nephrotoxic models (Pal et al., 2025; Mishra et al., 2014).

    Risk Factors for DrugInduced Nephrotoxicity

    Patient and treatment related risk factors are very strong determinants of the severity of drug induced nephrotoxicity. Old age, renal impairment that exists beforehand, diabetes, and hypertension predispose to the renal injury. Cumulative dosage, long term treatment and combination with other nephrotoxic agents increase risk further. Patients are also vulnerable to acute kidney injury due to such clinical conditions as dehydration, sepsis, or perioperative stress. Inter individual differences in renal toxicity could be attributed to genetic variation in the metabolism of drugs and the activity of drug transporters. The need to identify these risk factors is fundamental in customizing preventive measures and the need to consider adjunctive nephroprotective measures like B. diffusa in the vulnerable groups.

    CONCLUSION

    Drug induced nephrotoxicity reflects the convergence of multiple pathological signals, making singletarget interventions insufficient for durable renal protection. Thus, Boerhavia diffusa (Punarnava), with its diverse phytoconstituents, offers coordinated protection by enhancing antioxidant defenses, suppressing inflammation, preserving mitochondrial integrity, and limiting fibrosis. This multitargeted activity validates traditional claims and highlights Punarnava’s translational potential as a model plant for nephroprotection.

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    Robert, D. K., Govindan, L., Ramachandran, K., Sivanesan, S., Selvakumaran, K., & Rajadhinakaran, S. A. (2026). Nephroprotective Role of Boerhavia diffusa: A Mechanistic Review of Gene Expression and Signaling Cascades. Pharmacognosy Research, 18(4), 1187–1194. https://doi.org/10.5530/pres.20260077