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Anthocyanin-Rich Dark Sweet Cherry Phenolics Drive Context-Dependent Modulation of the Nrf2-Keap1-p62 Pathway in

Ana Nava-Ochoa¹, Rodrigo San-Cristobal¹, Susanne U Mertens-Talcott¹

¹Department of Food Science and Technology, Texas A&M University, College Station, TX 77843, USA.

|February 13, 2026

Abstract

Background/Objectives:

Triple negative breast cancer (TNBC) is an aggressive subtype treated primarily with chemotherapy, which often leads to drug resistance (DR) and reduced effectiveness. Phytochemicals, including anthocyanins from dark sweet cherry (ACN), have emerged as potential adjuvants to overcome DR, though mechanisms remain unclear. This study examines ACN effects on canonical and non-canonical antioxidant pathways (Nrf2-Keap1 and p62) as a mechanism to overcome DR in 4T1 TNBC cells with acquired DR.

Methods:

Two conditions were tested: ACN with basal doxorubicin (DOX) as resistance-maintaining conditions and ACN with DOX at IC₅₀ to induce oxidative stress (OS).

Results:

Under resistance-maintaining conditions, ACNs activated the canonical Nrf2-Keap1 pathway at high doses, which can potentially contribute to DR development due to its cellular protection effects. However, at a low dose, ACN did not trigger an antioxidant response linked to GST and GGT enzyme activities and instead impaired autophagy, increasing OS. Under OS, ACN activated the non-canonical antioxidant pathway mediated by p62 while deactivating Nrf2, leading to autophagy-induced cell death and further impairing autophagy at a low dose. Notably, inflammation persisted at both treatment levels without being relieved, keeping stress signaling active. At both conditions, ACN at doses likely attainable under physiological conditions effectively impaired autophagy and elevated OS, resulting in cell death.

Conclusions:

These results underscore the context-dependent dual function of polyphenols in cancer therapy, demonstrating their potential to enhance cellular sensitivity to chemotherapy and providing guidance for their strategic use as adjuvants in treating TNBC and overcoming DR. However, this study was limited to a single cell line derived from a murine model. Future research should include comparative studies using human TNBC cell lines to validate these findings and better assess their translational relevance.

Insights

Anthocyanins from dark sweet cherry (ACN) show dual effects on triple-negative breast cancer (TNBC) drug resistance (DR). Low-dose ACN impairs autophagy, increasing oxidative stress and cell death in TNBC cells.

Area of Science:

Biochemistry
Cell Biology
Cancer Research

Background:

Triple-negative breast cancer (TNBC) exhibits aggressive behavior and frequent chemotherapy drug resistance (DR).
Anthocyanins (ACN), phytochemicals from dark sweet cherry, are investigated for their potential to overcome DR.
The precise mechanisms by which ACN affects antioxidant pathways and DR in TNBC remain unclear.

Purpose of the Study:

To investigate the effects of anthocyanins (ACN) on canonical (Nrf2-Keap1) and non-canonical (p62) antioxidant pathways.
To elucidate the role of ACN in overcoming doxorubicin (DOX) resistance in 4T1 TNBC cells.
To understand how ACN influences autophagy and oxidative stress (OS) in the context of DR.

Main Methods:

Testing ACN with basal doxorubicin (DOX) under resistance-maintaining conditions.
Testing ACN with DOX at IC50 to induce oxidative stress (OS).
Assessing activation of Nrf2-Keap1 and p62 pathways, autophagy, and enzyme activities (GST, GGT).

Main Results:

High-dose ACN activated the canonical Nrf2-Keap1 pathway, potentially contributing to DR.
Low-dose ACN impaired autophagy, increased OS, and did not activate antioxidant enzymes.
Under OS, ACN activated p62, deactivated Nrf2, induced autophagy-related cell death, and impaired autophagy.
Inflammation persisted, and ACN at physiologically relevant doses impaired autophagy and elevated OS, leading to cell death.

Conclusions:

ACN exhibits context-dependent dual functions in cancer therapy, potentially enhancing chemotherapy sensitivity.
Strategic use of ACN as an adjuvant may help overcome DR in TNBC.
Findings are limited to a murine TNBC cell line; human cell line studies are needed for translational relevance.

Read full analysis

Keywords:

Nrf2-Keap1-p6w axis Prunus avium anthocyanins doxorubicin drug resistance in vitro model oxidative stress polyphenols redox signaling triple negative breast cancer

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