MOF promotes venous thromboembolism in lung cancer by activating the YBX1-MALT1-NF-κB-PAI-1 axis, possibly through histone crotonylation.

This study investigates the epigenetic regulation of venous thromboembolism (VTE) in lung cancer (LC), focusing on the role of the crotonylation enzyme males absent on the first (MOF). Utilizing bulk RNA sequencing (RNA-seq) and bioinformatics analysis of clinical LC-VTE samples, we identified MOF as a significantly upregulated protein modification-related gene. Further mechanistic exploration revealed that MOF was associated with histone H3K18 crotonylation (H3K18cr) and increased transcriptional expression of Y-box binding protein 1 (YBX1). YBX1 enhanced the stability of Mucosa-associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT1) mRNA, leading to increased MALT1 expression. MALT1 subsequently activated the NF-kappaB signaling pathway, where the subunit RELA directly bound to and upregulated the transcription of plasminogen activator inhibitor-1 (PAI-1). Elevated PAI-1 secretion by tumor cells drove a pro-coagulant state, ultimately contributing to VTE in LC patients. Both in vitro and in vivo models supported the involvement of the MOF/YBX1/MALT1/NF-kappaB/PAI-1 signaling axis. These findings suggest that MOF may promote LC-associated VTE possibly through histone crotonylation, thereby possibly linking histone crotonylation to hypercoagulability in LC.