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Review Open Access

Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review)

  • Authors:
    • Yanfang Zhang
    • Qingcai Li
    • Wenbin Yu
    • Bin He
    • Jiahua Peng
    • Bin Yao
  • View Affiliations / Copyright

    Affiliations: Geriatric Department ll, Shaoxing Seventh People's Hospital, Shaoxing, Zhejiang 312000, P.R. China, The Acupuncture Rehabilitation Center, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 334006, P.R. China, Jiangxi Key Laboratory of Natural Microbial Medicine Research, College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, P.R. China, School of Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 232
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    Published online on: April 14, 2026
       https://doi.org/10.3892/ol.2026.15587
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Abstract

Nobiletin, a polymethoxyflavone derived from Citrus peels, has emerged as a promising multi‑target anticancer agent. The present review consolidates recent advances elucidating the efficacy of nobiletin in suppressing tumor growth across diverse cancer types, including breast, colon, lung and gastric cancer. Mechanisms for inducing cell cycle arrest and apoptosis, inhibiting metastasis and angiogenesis, and modulating key oncogenic pathways, such as phosphatidylinositol 3‑kinase/protein kinase B/mechanistic target of rapamycin, mitogen‑activated protein kinase and nuclear factor‑κB are discussed. Crucially, the present review highlights the role of nobiletin in reversing chemoresistance and its synergistic potential with conventional therapeutics. Despite challenges in bioavailability, novel delivery strategies are paving the way for its clinical application. By reviewing current evidence, the present review underscores the notable potential of nobiletin as an integrative agent in oncology, offering a comprehensive perspective on its therapeutic prospects.
View Figures

Figure 1

Antitumor mechanisms of nobiletin.
The multifaceted antitumor effects of nobiletin, highlighting its
ability to inhibit cancer cell proliferation, induce apoptosis,
modulate autophagy, and suppress inflammation and angiogenesis.
Nobiletin targets key cell cycle proteins (CDK4, cyclin D1 and
CDK6) to arrest the cell cycle and induces apoptosis via caspase
activation. It also reduces oxidative stress by decreasing ROS and
modulates autophagy through proteins such as p62 and LC3.
Additionally, nobiletin inhibits metastasis and invasion by
suppressing MMP-9 and MMP-2, and upregulates miRNAs such as
miR-200b. ROS, reactive oxygen species; CDK, cyclin-dependent
kinase; MMP, matrix metalloproteinase; Bax, Bcl-2-associated X
protein; Bcl-2, B-cell lymphoma 2; Akt, protein kinase B; VEGF,
vascular endothelial growth factor; miR/miRNA, microRNA; JAZF1,
JAZF zinc finger 1; NF-κB, nuclear factor-κB; HIF-1α,
hypoxia-inducible factor 1α.

Figure 2

Nobiletin inhibits invasion and
migration of cancer cells through multiple pathways. Nobiletin, a
flavonoid compound, targets key pathways, including ERK-STAT,
PI3K/AKT, Wnt/p38/NF-κB/Nrf2, JNK, AKT/GSK-3β/β-catenin and
JAK2/STAT3. These pathways are crucial in regulating cancer cell
behaviors, such as proliferation, survival and migration. By
inhibiting the activation of these pathways, nobiletin reduces the
downstream signaling involved in cancer cell invasion and
metastasis. The diagram shows how nobiletin interferes with the
interaction between cancer cells and the extracellular matrix,
thereby preventing the detachment and migration of cancer cells
towards blood vessels, a critical step in metastasis. ERK,
extracellular signal-regulated kinase; STAT, signal transducer and
activator of transcription; PI3K, phosphatidylinositol 3-kinase;
AKT, protein kinase B; NF-κB, nuclear factor-κB; Nrf2, nuclear
factor erythroid 2-related factor 2; JNK, c-Jun N-terminal kinase;
GSK-3β, glycogen synthase kinase-3β; JAK2, Janus tyrosine kinase
2.

Figure 3

Mechanism of nobiletin-induced
apoptosis in cancer cells. Nobiletin activates multiple signaling
pathways, including IRE1-α/STAT3, ATF-4/CHOP/JAK2 and
PI3K/AKT/mTOR, leading to endoplasmic reticulum stress-mediated
apoptosis. It also causes DNA damage and increases ROS, activating
Bcl-2/Bax and caspase-3, ultimately leading to cell death.
Additionally, nobiletin arrests the cell cycle at the
G0/G1 phase by downregulating cyclin D1 and
CDK4, contributing to the inhibition of cell proliferation and
promotion of apoptosis. ROS, reactive oxygen species; Bcl-2, B-cell
lymphoma 2; Bax, Bcl-2-associated X protein; ATF-4, activating
transcription factor 4; CHOP, C/EBP homology protein; JAK2, Janus
tyrosine kinase 2; IRE1-α, inositol requiring enzyme 1-α; STAT3,
signal transducer and activator of transcription 3; PI3K,
phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR,
mechanistic target of rapamycin; CDK, cyclin-dependent kinase.

Figure 4

Overview of nobiletin's multi-target
mechanisms, drug resistance reversal and translational strategies
in cancer therapy. (A) Multi-target mechanisms: Nobiletin
simultaneously inhibits multiple oncogenic signaling pathways
(PI3K/AKT/mTOR, MAPK/ERK, NF-κB, Wnt/β-catenin and JAK2/STAT3),
leading to downstream effects, including cell cycle arrest,
apoptosis induction, metastasis inhibition and angiogenesis
suppression. (B) Overcoming drug resistance: Nobiletin targets four
distinct resistance mechanisms-efflux-mediated resistance (via MRP1
downregulation), EMT-associated resistance (via Notch-1/miR-200b
axis), cancer stem cell-related resistance (via Wnt/CD44v6
suppression) and immune escape (via PI3Kγ-mediated TAM
repolarization). (C) Therapeutic translation: Despite
bioavailability challenges (5–10% oral bioavailability and rapid
CYP450 metabolism), advanced delivery systems (nanoparticles, lipid
emulsions and oligosaccharide-based gels) are being developed to
facilitate clinical translation toward phase I/II trials and
combination therapy. PI3K, phosphatidylinositol 3-kinase; AKT,
protein kinase B; mTOR, mechanistic target of rapamycin; ERK,
extracellular signal-regulated kinase; MAPK, mitogen activated
protein kinase; NF-κB, nuclear factor-κB; JAK2, Janus tyrosine
kinase 2; STAT3, signal transducer and activator of transcription
3; miR, microRNA; TAM, tumor-associated macrophage; EMT,
epithelial-mesenchymal transition; CYP450, cytochrome p450; MRP1,
multidrug resistance-associated protein 1; MMP, matrix
metalloproteinase; CSC, cancer stem cell.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang Y, Li Q, Yu W, He B, Peng J and Yao B: Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review). Oncol Lett 31: 232, 2026.
APA
Zhang, Y., Li, Q., Yu, W., He, B., Peng, J., & Yao, B. (2026). Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review). Oncology Letters, 31, 232. https://doi.org/10.3892/ol.2026.15587
MLA
Zhang, Y., Li, Q., Yu, W., He, B., Peng, J., Yao, B."Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review)". Oncology Letters 31.6 (2026): 232.
Chicago
Zhang, Y., Li, Q., Yu, W., He, B., Peng, J., Yao, B."Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review)". Oncology Letters 31, no. 6 (2026): 232. https://doi.org/10.3892/ol.2026.15587
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang Y, Li Q, Yu W, He B, Peng J and Yao B: Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review). Oncol Lett 31: 232, 2026.
APA
Zhang, Y., Li, Q., Yu, W., He, B., Peng, J., & Yao, B. (2026). Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review). Oncology Letters, 31, 232. https://doi.org/10.3892/ol.2026.15587
MLA
Zhang, Y., Li, Q., Yu, W., He, B., Peng, J., Yao, B."Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review)". Oncology Letters 31.6 (2026): 232.
Chicago
Zhang, Y., Li, Q., Yu, W., He, B., Peng, J., Yao, B."Nobiletin in cancer therapy: Emerging insights into multi-target mechanisms, overcoming drug resistance and therapeutic translation (Review)". Oncology Letters 31, no. 6 (2026): 232. https://doi.org/10.3892/ol.2026.15587
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