RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy

Background Alternative splicing of pre‐mRNA is a fundamental regulatory process in multicellular eukaryotes, significantly contributing to the diversification of the human proteome. RNA‐binding fox‐1 homologue 2 (RBFOX2), a member of the evolutionarily conserved RBFOX family, has emerged as a critical splicing regulator, playing a pivotal role in the alternative splicing of pre‐mRNA. This review provides a comprehensive analysis of RBFOX2, elucidating its splicing activity through direct and indirect binding mechanisms. RBFOX2 exerts substantial influence over the alternative splicing of numerous transcripts, thereby shaping essential cellular processes such as differentiation and development. Main body of the Dysregulation of RBFOX2‐mediated alternative splicing has been closely linked to a spectrum of cardiovascular diseases and malignant tumours, underscoring its potential as a therapeutic target. Despite significant progress, current research faces notable challenges. The complete structural characterisation of RBFOX2 remains elusive, limiting in‐depth exploration beyond its RNA‐recognition motif. Furthermore, the scarcity of studies focusing on RBFOX2‐targeting drugs poses a hindrance to translating research findings into clinical applications. Conclusion This review critically assesses the existing body of knowledge on RBFOX2, highlighting research gaps and limitations. By delineating these areas, this analysis not only serves as a foundational reference for future studies but also provides strategic insights for bridging these gaps. Addressing these challenges will be instrumental in unlocking the full therapeutic potential of RBFOX2, paving the way for innovative and effective treatments in various diseases. RNA‐binding fox‐1 homologue 2 (RBFOX2) binds to RNA, influencing splicing and recruiting PRC2 for transcriptional repression. RBFOX2 impacts electromyographic signalling, L‐type Ca2+ channels, sliding filaments and mitochondria. RBFOX2 is involved in tumour cell proliferation, invasion, migration and drug resistance. Targeting RBFOX2 with compounds, such as T‐1101 tosylate and RNA‐PROTACs, shows promise for treating related diseases. CTD, C‐terminal domain; PRC2, polycomb repressive complex 2; PROTAC, proteolysis‐targeting chimeras; RRM, RNA‐recognition motif. Created with BioRender.com.