Fibronectin 1 mediated histone lactylation promotes malignant progression of GIST regulated by m6A modification

Abstract The malignant progression of gastrointestinal stromal tumors (GISTs) and the high incidence of Imatinib (IM) resistance currently pose significant challenges to the treatment of GISTs, whose underlying molecular mechanisms remain largely unknown. Hence, there is an urgent need to examine mechanisms that may provide innovative understanding relevant to clinical therapies. In this study, we confirm that FN1 is a key protein in GIST progression and observe a significant IM sensitization effect in IM-resistant FN1 knockout cells, with validation both in vitro and in vivo. What’s more, FTO is found to reduce m⁶A modification at the 631st site of FN1 mRNA through demethylation, thereby protecting FN1 mRNA from recognition and degradation by YTHDF3. Simultaneously, we find that elevated FN1 expression is positively correlated with the glycolytic pathway, thereby promoting lactate production. The histone H3 lysine 18 lactylation (H3K18la) levels are upregulated by FN1, which activates the transcription of KIT, thereby driving the malignant progression of GISTs and inducing IM resistance. In conclusion, this study proposes a potential therapeutic strategy by targeting FN1 to suppress GIST progression and overcome IM resistance.