Emerging STAT1 post-translational modifications: mechanisms and translational perspectives.

Signal transducer and activator of transcription 1 (STAT1) is a central regulator of interferon signaling, antiviral defense, inflammation, and antitumor immunity. Although STAT1 activation has been traditionally defined by phosphorylation, recent studies have revealed diverse post-translational modifications (PTMs) that fine-tune its activity, stability, localization, and transcriptional output. Newly identified modifications, including vitamin C-derived vitcylation and pyruvate-induced pyruvylation, directly link nutrient and metabolic cues to STAT1 signaling. Additional PTMs, such as acylation, glycosylation, ubiquitination, methylation, and oxidative modifications, further shape STAT1 function in a context-dependent manner. In this review, we evaluate the evidence supporting STAT1 PTMs and discuss how specific modifications regulate STAT1 activation, stability, localization, and transcriptional output in immune and inflammatory contexts, while distinguishing established regulatory mechanisms from emerging modifications that require further validation.