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Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with a poor prognosis that requires novel therapeutic agents. Proteome information is useful for identifying new therapeutic candidates because it directly reflects the biological phenotype. Additionally, in vitro drug screening is an effective tool to identify candidate drugs for common cancers. Hence, we attempted to identify novel therapeutic candidates for MPNST by integrating proteomic analysis and drug screening. We performed comprehensive proteomic analysis on 23 MPNST tumor samples using liquid chromatography – tandem mass spectrometry to identify therapeutic targets. We also conducted drug screening of six MPNST cell lines using 214 drugs. Proteomic analysis revealed that the MET and IGF pathways were significantly enriched in the local recurrence/distant metastasis group of MPNST, whereas drug screening revealed that 24 drugs showed remarkable antitumor effects on the MPNST cell lines. By integrating the results of these two approaches, MET inhibitors, crizotinib and foretinib, were identified as novel therapeutic candidates for the treatment of MPNST. We successfully identified novel therapeutic candidates for the treatment of MPNST, namely crizotinib and foretinib, which target the MET pathway. We hope that these candidate drugs will contribute to the treatment of MPNST. [ABSTRACT FROM AUTHOR]

• The GSH oxidase-like activity of MIL-53 depletes GSH, overcoming ferroptosis resistance in tumors. • The catalase-like activity of MIL-53 boosts photodynamic therapy by generating oxygen through the decomposition of H 2 O 2. • The photodynamic effect of MMSC generates singlet oxygen, further amplifying ferroptosis. • cMBP peptide modification attenuates MET pathway in MET-overexpressing tumors, reducing antioxidant capacity and promoting ferroptosis. • Transcriptomic analysis revealed that MMSC modulates the expression of ferroptosis-related and MET signaling pathways-related genes. Ferroptosis, a relatively recently discovered form of programmed cell death, has garnered considerable attention in the field of cancer drug discovery. However, effectively inducing ferroptosis at tumor sites and maximizing its therapeutic efficacy remains a formidable challenge. In the present study, we constructed the MIL-53@cMBP@ST/Ce6 (MMSC) nanocomplex to enhance the therapeutic efficacy of a ferroptosis-inducing drug. This was accomplished by modifying the cMBP peptide and encapsulating a small molecular ferroptosis inducer, sorafenib tosylate (ST), along with a photosensitizer, Chlorin e6 (Ce6), within the iron-based nanozyme MIL-53, which exhibits multiple enzyme-like activities. The glutathione (GSH) oxidase-like activity of MIL-53 depletes GSH, which is known to contribute to ferroptosis resistance in tumors. The catalase-like activity of MIL-53 catalyzes the decomposition of H 2 O 2 within the tumor, yielding oxygen to enhance the effect of photodynamic therapy. Concurrently, the photodynamic effect of MMSC generates singlet oxygen (1O 2), further amplifying ferroptosis. Additionally, modification of the cMBP peptide enabled MMSC to attenuate the MET pathway in MET-overexpressing tumors, thereby decreasing the antioxidant capacity of these cells to promote ferroptosis. Notably, transcriptomic analysis revealed that PDT enhances the ferroptosis pathway and modulates the expression of ferroptosis-related genes and MET signaling pathways-related genes, while Western Blot results confirmed the inhibition of GPX4 protein, a critical regulator of ferroptosis. In vivo, MMSC demonstrated a tumor-specific accumulation effect, as evidenced by fluorescence imaging, and significantly inhibited tumor growth by alleviating the hypoxic tumor microenvironment and enhancing ferroptosis at the tumor site. This study presents a novel strategy for the mechanistic investigation of augmented ferroptosis in tumor therapy. [ABSTRACT FROM AUTHOR]