Abstract
This study aimed to investigate the molecular mechanism by which propofol enhances chemosensitivity in non-small cell lung cancer (NSCLC). In vitro experiments were performed to evaluate the effects of propofol on NSCLC cell lines and to elucidate the underlying molecular mechanisms. In vivo, A549/DDP cells were subcutaneously injected into nude mice, followed by cisplatin (DDP) treatment, and tumor tissues were subsequently analyzed by hematoxylin–eosin staining and immunohistochemistry. Our results demonstrated that propofol significantly enhanced the sensitivity of A549/DDP cells to cisplatin by promoting Parthanatos. This process was characterized by increased apoptosis-inducing factor (AIF) and macrophage migration inhibitory factor (MIF) binding and nuclear translocation, loss of mitochondrial membrane potential, nicotinamide adenine dinucleotide (NAD+) depletion, accumulation of poly(ADP-ribose) (PAR), and increased expression of the DNA damage marker phosphorylated histone H2AX (γH2AX). Moreover, propofol treatment was associated with elevated interleukin-6 (IL-6) levels. Mechanistically, overexpression of methyltransferase-like 3 (METTL3) enhanced PARP-1 m6A modification and Parthanatos activation, whereas METTL3 knockdown exerted the opposite effects. Furthermore, propofol enhanced cisplatin sensitivity by regulating METTL3-mediated m6A modification of PARP-1 in vitro, which was further confirmed in vivo. In conclusion, propofol enhances cisplatin chemosensitivity in NSCLC by activating Parthanatos through modulation of METTL3-mediated PARP-1 m6A modification. These findings provide mechanistic insight into propofol-mediated reversal of chemoresistance and identify the METTL3–PARP-1–Parthanatos axis as a potential therapeutic target in NSCLC.
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All data in this study are available from the corresponding author on reasonable request.
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The authors express their appreciation to staff in Zhongshan People’s Hospital, for their technical assistance.
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Quan Ling, Yong Chen: study design, data analysis, drafting the manuscript and revision of the manuscript. Kepeng Liu, Junlin Wen, Jin Liu: data collection and analysis, drafting the manuscript, investigation. All authors read and approved the final version of the manuscript.
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Our study has been approved by laboratory animal care and ethics committee of Guangdong Laidi Biomedical Research lnstitute Co, LTD (Approval No. 2024027-3).
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Ling, Q., Liu, K., Wen, J. et al. Propofol regulates METTL3-mediated PARP-1 m6A modification to promote Parthanatos to improve NSCLC chemotherapy resistance. Sci Rep (2026). https://doi.org/10.1038/s41598-026-42665-y
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DOI: https://doi.org/10.1038/s41598-026-42665-y
