Magnolol facilitates mitochondrial-peroxisome dysfunction and induces oxeiptosis in lung cancer cells following transfer via tunneling nanotubes - 17/05/25

Doi : 10.1016/j.biopha.2025.118126

Meng-Hsuan Cheng ^a,^b,^c, Hsiao-Hsuan Wang ^d, Mo Da-Sang Hua ^e, Hsuan-Fu Kuo ^f,^g,^h, Zi-Jing Lin ^e, Chong-Chao Hsieh ^i,^j,^k, Chih-Hsin Hsu ^d,^l, Chia-Yang Li ^m, Shu-Chi Wang ⁿ, Yung-Hsiang Chen ^o,^p, Szu-Hui Wu ^b,^m, Wei-Lun Liu ^q,^r,^s,^⁎ , Po-Len Liu ^b,^t,^u,^⁎
^a School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^b Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^c Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, ROC
^d Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC
^e National Synchrotron Radiation Research Center, Hsinchu 300, Taiwan, ROC
^f Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^g Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Gangshan Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^h Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
ⁱ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^j Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^k Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^l Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC
^m Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
ⁿ Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
^o Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan, ROC
^p Department of Psychology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan, ROC
^q School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan, ROC
^r Department of Critical Care Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei 243, Taiwan, ROC
^s Data Science Center, College of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan, ROC
^t Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, ROC
^u Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC

^⁎Corresponding author at: School of Medicine, College of Medicine, Fu Jen Catholic University, No.510, Zhongzheng Rd., Xinzhuang Dist., New Taipei 242062, Taiwan, ROC.School of Medicine, College of Medicine, Fu Jen Catholic UniversityNo.510, Zhongzheng Rd., Xinzhuang Dist.New Taipei242062Taiwan, ROC^⁎⁎Correspondence to: Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Rd., Sanmin Dist., Kaohsiung 807378, Taiwan, ROC.Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical UniversityNo.100, Shih-Chuan 1st Rd., Sanmin DistKaohsiung807378Taiwan, ROC

Abstract

Recent therapeutic advances have improved survival rates for patients with lung cancer. However, drug resistance remains a significant challenge and is closely linked to mitochondrial alterations in lung cancer cells. Magnolol, a compound extracted from Magnolia officinalis, has anti-cancer properties. However, its impact on mitochondria in cancer cells remains poorly understood. This study aimed to explore the therapeutic potential of Magnolol in lung cancer and elucidate its effects on mitochondria in lung cancer cells. The effects of Magnolol on lung cancer were studied using xenograft mouse studies and in vitro analyses. Magnolol promotes the production of reactive oxygen species (ROS) and inhibits the antioxidant pathway in cancer cells. This disruption further impairs redox interactions between mitochondria and peroxisome, leading to mitochondrial dysfunction and mitocytosis. Additionally, Magnolol activates oxeiptosis, facilitating intercellular transport of damaged mitochondria and peroxisomes via tunneling nanotubes. The increased fusion of mitochondria may contribute to mitochondrial dysfunction, promote the accumulation of dysfunctional peroxisomes in recipient cells, and elevate ROS levels. In turn, this process enhances oxeiptosis, ultimately inhibiting tumour progression. These findings suggest that Magnolol may serve as a promising targeted therapeutic for disrupting mitochondrial function in lung cancer.

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Graphical Abstract

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Highlights

•	Magnolol inhibits the KEAP1-NRF2-mediated antioxidant response.
•	Magnolol induces mitochondrial damage and dysfunction in lung cancer cells.
•	Magnolol promotes mitochondrial and peroxisomal transfer via tunneling nanotubes.
•	Magnolol exerts anti-cancer effects by inducing oxeiptosis in lung cancer cells.
•	Magnolol is a promising therapeutic agent for the treatment of lung cancer.

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Abbreviations : AIFM1, ARE, GPX1, HBEC, HO-1, KEAP1, NRF2, NSCLC, OCR, PGAM5, Redox, ROS, SEM, SOD2, SXT: soft X-ray tomography, TNT

Keywords : Lung cancer, Magnolol, Mitochondria, Oxeiptosis, Tunneling nanotubes

Plan

Introduction

Materials and methods

Cell culture

Cell viability assay

Subcutaneous xenograft lung cancer model establishment

Western blot (WB)

Immunohistochemical staining (IHC)

Fluorescence staining

Flow cytometry

Mitochondrial energy metabolism measurement

Field-emission scanning electron microscopy (SEM)

Field emission-transmission electron microscopy (TEM)

Gene silencing

Real-time PCR

Soft X-ray tomography (SXT)

Survival analysis

Statistical analysis

Results

Magnolol attenuates the NRF2-ARE-mediated antioxidant response

Magnolol induces mitochondrial damage and dysfunction and inhibits mitophagy

Magnolol facilitates the clearance of damaged mitochondria via mitocytosis

Magnolol promotes mitochondria transfer between lung cancer cells through TNTs using mitochondria-associated motor proteins

Magnolol enhances mitochondria transfer and fusion through TNTs

Magnolol disrupts the redox interplay between mitochondria and peroxisome by downregulating catalase expression

Magnolol exerts anti-cancer effects via oxeiptosis in lung cancer cells

Magnolol exerts anti-cancer effects in NSCLC

Discussion

Conclusion

CRediT authorship contribution statement

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Funding

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Vol 187

Article 118126- juin 2025 Retour au numéro

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Magnolol facilitates mitochondrial-peroxisome dysfunction and induces oxeiptosis in lung cancer cells following transfer via tunneling nanotubes - 17/05/25

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