Mitophagy is a selective autophagic process responsible for removing damaged mitochondria. In a recent review, Chinese researchers explored the molecular mechanisms that govern mitophagy and its aberrant role in the onset and progression of breast cancer. It offers a detailed overview of the dual functions of mitophagy in breast cancer advancement, investigates the potential of mitophagy-related genes and proteins as biomarkers and therapeutic targets, and emphasizes the significance of mitophagy regulators in enhancing treatment outcomes .
Breast cancer (BC) persists as the predominant malignancy affecting women globally, with surveillance data documenting approximately 2.3 million new diagnoses and 685,000 fatalities in 2020. Epidemiological projections indicate a rising trajectory, with annual incidence anticipated to reach 3 million cases by 2040. Notwithstanding considerable advances in multimodal therapeutic regimens—encompassing surgery, chemotherapy, radiotherapy, endocrine therapy, immunotherapy, and molecularly targeted agents—the emergence of drug resistance and disease relapse constitutes a major clinical impediment, underscoring the imperative for novel therapeutic interventions. Mitophagy, an evolutionarily conserved selective autophagic process responsible for the lysosomal degradation of damaged mitochondria, serves as a pivotal mechanism for cellular homeostasis, yet manifests context-dependent duality in BC pathogenesis. Although mitophagy can exert tumor-suppressive effects during early oncogenesis by alleviating oxidative stress and preserving genomic integrity, advanced malignancies frequently co-opt this pathway to sustain metabolic adaptation and thrive within hostile microenvironments, such as hypoxic niches. Present understanding of mitophagy regulation remains fragmented, necessitating a systematic elucidation of its molecular determinants and clinical translational potential in BC.
To bridge this conceptual and translational gap, Professor Zhang Zhang and her research team from the Department of Pathology at West China Hospital, Sichuan University, China, have constituted a comprehensive review that synthesizes contemporary insights into the regulatory architecture of mitophagy and its multifaceted involvement in BC initiation, progression, and therapeutic response. This scholarly work methodically delineates fundamental mitophagy pathways, critically appraises mitophagy-associated molecules as putative biomarkers and therapeutic targets, and synthesizes emerging strategies for therapeutically harnessing mitophagy in BC management. The article is published in the Chinese Medical Journal on 25 December 2025.
Mitophagy plays an integral role in BC initiation, progression, immune microenvironment regulation, and treatment response through both Parkin-dependent and Parkin-independent pathways. Key regulators, including PINK1, Parkin, BNIP3, FUNDC1, MUL1, ARIH1, and p62, frequently exhibit mutations or aberrant expression in BC and are closely associated with disease progression and prognosis, highlighting their potential as prognostic biomarkers and therapeutic targets. Recent advances, such as the low-toxicity mitochondrial-targeted fluorescent biosensor PMV-12, offer novel tools for visualizing BC lung metastases. Moreover, mitophagy influences tumor metabolism and immune cell activity, with its gene expression patterns predicting patient prognosis and immunotherapy response. Notably, mitophagy exhibits a dual nature: while it suppresses tumor initiation by eliminating damaged mitochondria in early stages, excessive or dysregulated mitophagy in advanced disease can promote cancer cell survival, invasion, and therapy resistance.
"The dual role of mitophagy presents both a challenge and an opportunity. Understanding the specific context — whether mitophagy is protective or destructive — is key to developing targeted therapies , " explains Prof. Zhang.
In the context of BC treatment, both the inhibition and activation of mitophagy may serve as therapeutic strategies. For example, fenbendazole has been shown to inhibit BC cell proliferation and migration by activating mitophagy. Additionally, mitochondrial-targeted nanodrugs, natural compounds, and innovative targeted therapies exert anti-tumor effects through the regulation of mitophagy. Compounds such as urolithin A and cyclovirobuxine D induce mitophagy by activating the TFEB and FOXO3a/PINK1/Parkin pathways, respectively. Within a multidisciplinary treatment framework, strategic modulation of mitophagy can enhance the precision and personalization of BC treatment when combined with other therapeutic modalities.
Currently, research on mitophagy in BC remains largely preclinical. Some mitophagy regulators, including terazosin and idebenone, have progressed to clinical trials primarily for neurodegenerative diseases and metabolic disorders, offering valuable insights for potential clinical applications in BC. However, several limitations persist in this research area: (1) an incomplete understanding of mitophagy mechanisms across various BC subtypes; and (2) a scarcity of specific targeted drugs. Future research should focus on developing small-molecule drugs or nanoparticle therapies for precise mitophagy modulation, employing CRISPR gene editing and single-cell analysis to clarify its mechanisms, identifying signaling pathways in different BC subtypes, discovering biomarkers for predicting treatment responses, and exploring combination strategies with chemotherapy, immunotherapy, or targeted therapy. Advancing these research avenues holds significant promise for overcoming treatment resistance, improving patient prognosis, and fostering breakthroughs and renewed hope in BC therapy.
"Targeting mitophagy opens new avenues for personalized medicine in BC. Future research should focus on defining the role of mitophagy in different BC subtypes and developing specific modulators that can be integrated with existing treatments to overcome resistance , " concludes Prof. Zhang about the promising potential of mitophagy.
About Zhang Zhang from Sichuan University, China
Professor Zhang Zhang is a Chief Physician, PhD, Master's Supervisor, Director of the Department of Pathology at West China Tianfu Hospital, Sichuan University, and Deputy Director of the Clinical Pathology Research Institute at West China Hospital, Sichuan University. As a selected academic leader in healthcare, she has authored over 50 scientific publications and led several national and provincial research projects. Professor Zhang also holds prominent roles in professional societies including the Chinese Society of Pathology and the Chinese Anti-Cancer Association and several pathology and oncology academic committees.
Chinese Medical Journal
Literature review
Not applicable
Mitophagy in breast cancer: Regulatory mechanisms and therapeutic potential
25-Dec-2025
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