What does ETV4 really do in human diseases: emerging roles, mechanisms, and therapeutic perspectives

Transcription factor ETV4 is a member of the E26 transformation-specific (ETS) family and has recently emerged as a pivotal regulator in various diseases, functioning as a dynamic transcriptional integrator that links extracellular signaling cues to chromatin remodeling and transcriptional reprogramming. Accumulating evidence has expanded its functional spectrum far beyond conventional growth control, revealing critical roles in ferroptosis suppression, DNA damage, metabolic reprogramming, stemness maintenance, immune evasion, and tumor microenvironment regulation. In this review, we present a conceptual synthesis of current advances in ETV4 biology, emphasizing emerging mechanistic insights that redefine its role across cancer and nonmalignant disease contexts. We further highlight emerging insights into its potential involvement in phase separation and cancer neuroscience, proposing that ETV4 may serve as a molecular bridge integrating neural, immune, and metabolic cues within malignant contexts. By situating these recent developments within the broader landscape of cancer research, we outline unresolved challenges and offer new perspectives for the precision targeting of “undruggable” transcription factors, aiming to facilitate the translation of ETV4 from basic discovery to clinical application.