Lactylation‐Driven PROS1‐TYRO3‐CARF Signaling Promotes Therapy‐Induced Senescence Escape and Radioresistance in Meningioma

Radiotherapy is a major treatment for meningioma, but radioresistance remains a key obstacle to durable disease control. Here, we show that escape from therapy-induced senescence (TIS) is a hallmark of radioresistant meningioma cells and identify a novel glycolysis-H3K27 lactylation-PROS1-TYRO3-CARF axis underlying this phenotype. Using photon-derived radioresistant meningioma models established from two independent meningioma cell lines, combined with multi-omics, CUT&Tag, dual‑luciferase reporter assays, immunoprecipitation-mass spectrometry, and in vivo xenograft analyses, we found that radioresistant cells display enhanced glycolysis, lactate accumulation, and increased H3K27 lactylation. H3K27la promotes PROS1 transcription, leading to PROS1 secretion and TYRO3 activation. Activated TYRO3 in turn promotes phosphorylation of CARF at tyrosine 8 and triggers its proteasomal degradation, relieving CDKN2A/p53-associated senescence, and permitting cell cycle re-entry. Disruption of PROS1 signaling or inhibition of CARF phosphorylation restores senescence-associated phenotypes and enhances radiosensitivity in vivo. Together, these findings establish a metabolic-epigenetic-signaling mechanism that couples glycolytic reprogramming to TIS escape in meningioma and highlight the PROS1-TYRO3-CARF axis as a potential radiosensitizing target.