TET2 in Sepsis-Induced ICU-Acquired Weakness: Regulatory Role in the “Inflammation-Metabolism-Autophagy” Axis and Clinical Implications

Sepsis-induced ICU-acquired weakness (ICU-AW) is a major complication in critically ill patients, contributing to prolonged mechanical ventilation, increased mortality, and long-term functional impairment. Emerging evidence highlights that epigenetic dysregulation, particularly through DNA demethylation mediated by Ten-Eleven Translocation 2 (TET2), plays a pivotal role in the pathogenesis of ICU-AW. TET2 catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby contributing to the regulation of gene expression networks involved in inflammation, metabolism, and autophagy. In the septic microenvironment, inflammatory cytokines suppress TET2 expression via the NF-κB pathway, which may contribute to disrupted homeostasis of the “inflammation-metabolism-autophagy” axis and is associated with muscle atrophy and dysfunction. This review systematically outlines the basic biology of TET2, its regulation under septic conditions, and the potential mechanisms by which it may contribute to ICU-AW through the aforementioned axis. Furthermore, we discuss the translational potential of TET2 as a diagnostic biomarker and a target for therapeutic interventions, including small-molecule agonists, epigenetic editing, and nutritional strategies. Although tissue-specific delivery and long-term safety remain critical hurdles, TET2-targeted strategies may enable precision management of sepsis-induced ICU-AW.