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Pip3.0
Piperlongumine Research
Mostly mechanism / observationalLimited safety
18 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Piperlongumine studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality studies published 2013–2026.
Based on 18 studies
Confidence
Low
By outcome
Safety profile
Mostly mechanism / observational7 studies
Cancer (preclinical)
Mostly mechanism / observational5 studies
Senescence & healthspan (preclinical)
Too few graded studies2 studies
Active research area
13 studies in the last 5 years
201320192026
1Systematic Review2025
Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management.
Lee J, Roh JL. · Cells (2025)
Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues.
Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers.
Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity.
By bridging ancient knowledge with modern innovations, this review highlights P. longum as a versatile candidate for integrative medicine and novel drug delivery strategies.
Bhatia A, Mehta J, Hashmi AR, Sekar M, Bandyopadhyay A, Pal T, Kumar BRP, Mat Rani NNI, Wong LS, Kumarasamy V. · Drug design, development and therapy (2026)
Furthermore, advances in nanotechnology including liposomes, cubosomes, and transgelosomes, have enhanced its solubility, bioavailability, and targeted pharmacological efficacy.
Industrial applications span nutraceuticals, phytopharmaceuticals, and green nanotechnology, underscoring its potential for commercialization.
Clinical and preclinical studies validate its efficacy and safety within therapeutic ranges.
The compound's favorable drug-likeness, oral bioavailability, and selective toxicity profile highlight its potential as a multitarget scaffold for the development of next-generation therapeutics against neglected tropical and immune-related diseases.
Fukui-Silva L, Souza FCR, Amorim CS, de Moraes J. · Journal of immunology research (2026)
The compound's favorable drug-likeness, oral bioavailability, and selective toxicity profile highlight its potential as a multitarget scaffold for the development of next-generation therapeutics against neglected tropical and immune-related diseases.
Studies on Schistosoma mansoni, Angiostrongylus cantonensis, Leishmania spp., Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii demonstrate potent activity at micromolar levels, associated with disruption of parasite redox homeostasis.
In host immune cells, piplartine modulates NF-κB and Nrf2 signaling, inhibits the immunoproteasome, and promotes antioxidant and anti-inflammatory responses.
In this review, the anticancer activity of some potent bioactive compounds such as curcumin (CUR), guggulsterone (GUG), resveratrol (RES), garcinol (Gal), verrucarin A (Ver-A), berberine (BBR), celastrol (CeL), baicalein (BaI), capsaicin (CAP), galangin (GA), kaempferol (KaE), piperlongumine (PL), licochalcone-A (LiC-A), Rg3, and saffron (SAF) with special preference to ER modulation in liver cancer have been presented briefly.
Sharma N, Gupta M, Guleria M, Anand M, Malhan A, Chitme HR, Singh S, Sarwat M. · Chemistry & biodiversity (2025)
Extracellular factors, such as hypoxia, nutrient distress, and pH imbalance, cause alteration in endoplasmic reticulum (ER) homeostasis, which, in turn, accumulates misfolded and unfolded proteins in the lumen of ER selectively recognized as ER-stress.
Impairment of ER homeostasis activates the cascade of signaling events called un-folded protein response (UPR).
In recent years, a greater variety of phytopharmaceutical derived from plants have been used alongside conventional chemotherapeutic agents to manage liver cancer.
Current literature supports the continued exploration of cinnamic acid derivatives as promising candidates for cosmetic products targeting skin hyperpigmentation.
Kabat M, Gunia-Krzyżak A. · Chemistry & biodiversity (2025)
Reliable evidence supporting the efficacy of these compounds comes from advances in vitro models, such as 3D cell cultures and pigmented reconstructed human epidermis.
However, clinical confirmation remains limited.
To date, p-coumaric acid and extracts from bird's nest fern and pomegranate peel have been clinically evaluated.
These efforts could significantly advance the role of phytocompounds in breast cancer management.
Wali AF, Pillai JR, Talath S, Shivappa P, Sridhar SB, El-Tanani M, Rangraze IR, Mohamed OI, Al Ani NN. · Current issues in molecular biology (2025)
Besides, the study also covers the potential adverse effects of these phytochemicals.
Regarding mechanisms, the widest attention is paid to Complementary and synergistic strategies are discussed which indicate that it would be realistic to alter the dosage and delivery systems of liposomes, nanoparticles, nanoemulsions, and films to enhance efficacy.
Future research directions include refining these delivery approaches, further elucidating molecular mechanisms, and conducting clinical trials to validate findings.
Moreover, this review is expected to provide a reference for the development and application of PL in the anti-tumor therapies.
Zhang HX, Lin LF, Liu YL, Li H. · Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica (2024)
To improve the application of PL in the clinical treatment of tumors, researchers have constructed various nano-drug delivery systems to increase the efficiency of PL delivery.
This paper reviewed the physicochemical properties, anti-tumor mechanism, combined therapies, and nano-drug delivery systems of PL in recent years.
Moreover, this review is expected to provide a reference for the development and application of PL in the anti-tumor therapies.
An attempt to understand the future prospects and direction of research about the compound has also been discussed.
Mitra S, Biswas P, Bandyopadhyay A, Gadekar VS, Gopalakrishnan AV, Kumar M, Radha, Nandy S. · Naunyn-Schmiedeberg's archives of pharmacology (2024)
Since BC cells resist conventional chemotherapeutic drugs (doxorubicin, docetaxel etc.), researchers have shown that the drugs in combination with PL can exhibit a synergistic effect, greater than the effects of the drug or PL alone.
Recently, techniques for drug packaging based on nanotechnology have been employed to improve PL release.
The review has presented an outline of the chemistry of PL, its molecular basis in BC, its bioavailability, toxicity, and nanotechnological applications.
In summary, alkaloids represent a promising avenue for targeting the dysregulated PAMT pathway in cancer, and further research is warranted.
Mokhfi FZ, Al Amin M, Zehravi M, Sweilam SH, Arjun UVNV, Gupta JK, Vallamkonda B, Balakrishnan A, Challa M, Singh J, Prasad PD, Ali SS, Ahmad I, Doukani K, Emran TB. · Chemico-biological interactions (2024)
In glioblastoma models, harmine suppresses mTORC1.
This review focuses on alkaloids such as evodiamine, hirsuteine, chaetocochin J, indole-3-carbinol, noscapine, berberine, piperlongumine, and so on, which have shown promise in targeting the PAMT pathway.
Clinical studies evaluating alkaloids as part of cancer treatment are underway, and their potential impact on patient outcomes is being investigated.
Far from being benign, plant-derived agents exert potent immune effects that could either complement or compromise modern immunotherapy, underscoring the need for rigorous evaluation.
Beier V, Wink M, Samstag Y. · Advances in biological regulation (2026)
EGCG, the major polyphenol in green tea, downregulates PD-L1 expression and augments anti-tumor immunity in murine melanoma.
We critically assess the promise and pitfalls of these compounds in cancer immunotherapy, emphasizing mechanistic insights, pharmacokinetics, translational hurdles, and potential risks of interfering with established therapies.
A precision immunology framework - integrating immune monitoring, patient stratification, and controlled clinical trials - will be essential to determine whether phytochemicals can be safely and effectively incorporated into oncology.
We will also provide a survey on their potential in therapeutic perspectives of age-related diseases.
Dotou M, L'honoré A, Moumné R, El Amri C. · Journal of natural products (2024)
Among them, Piper alkaloids have emerged as interesting candidates in the context of age-related diseases and particularly senescence.
These compounds have been shown to display a variety of features, including antioxidant, anti-inflammatory, neuroprotective, and other bioactive properties that may help counteracting the effects of cellular aging processes.
In the review, we will put the emphasis on piperlongumine and other related derivatives, which belong to the Piper alkaloids, and whose senomodulating potential has emerged during the last several years.
The number of potential clinical applications of agents targeting NR4A is increasing and this should spur future development of SNR4AMs as therapeutics that act through NR4A1, NR4A2 and NR4A3.
Safe S. · Histology and histopathology (2024)
Ligands that bind NR4A1, NR4A2, and NR4A3 including Cytosporone B, celastrol, bis-indole derived (CDIM) compounds, tryptophan/indolic, metabolites, prostaglandins, resveratrol, piperlongumine, fatty acids, flavonoids, alkaloids, peptides, and drug families including statins and antimalarial drugs.
The structural diversity of NR4A ligands and their overlapping and unique effects on NR4A1, NR4A2, and NR4A3 suggest that NR4A ligands are selective NR4A modulators (SNR4AMs) that exhibit tissue-, structure-, and response-specific activities.
The SNR4AM activities of NR4A ligands are exemplified among the Cytosporone B analogs where n-pentyl-2-[3,5-dihydroxy-2-(nonanoyl)]phenyl acetate (PDNPA) binds NR4A1, NR4A2 and NR4A3 but activates only NR4A1 and exhibits significant functional differences with other Cytosporone B analogs.
Piperlongumine shows selective preclinical anticancer activity via ROS accumulation and glutathione depletion, with nanoformulation needed to overcome poor bioavailability.
Tripathi, Biswal · Pharmacological research (2020)
Piplartine is selectively cytotoxic to cancer cells via oxidative stress and inhibits tumor growth in mice, with chronic toxicology still needed before clinical trials.
Bezerra, Pessoa, de Moraes, Saker-Neto, Silveira, Costa-Lotufo · European journal of pharmaceutical sciences (2013)
Foundational review of piplartine/piperlongumine's chemistry and broad preclinical pharmacology
Anticancer activity (selective oxidative-stress-driven cytotoxicity, antitumor in mice) is its most promising property
Flags that chronic toxicology is still needed to support clinical trials — i.e. no human efficacy yet
Piperlongumine and its derivatives show preclinical anticancer promise, with ongoing work on analogs and delivery to overcome pharmacokinetic limitations.
Swain, Sahoo · Archiv der Pharmazie (2024)
Recent review of piperlongumine and synthetic derivatives as anticancer leads
Summarizes the parent compound's mechanism and the push toward derivatives/delivery systems
Underscores that translation is limited by pharmacokinetics — still no clinical efficacy