Propofol regulates METTL3-mediated PARP-1 m6A modification to promote Parthanatos to improve NSCLC chemotherapy resistance

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.

Chemotherapy resistance; Non-small cell lung cancer; PARP-1; Parthanatos; Propofol; m6A.