STAT1: a central hub linking ferroptosis and inflammation in hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (HIRI) remains an intractable perioperative complication of liver transplantation and hepatectomy, driven by two interdependent but historically segregated pathological cascades: iron-dependent ferroptotic parenchymal death and amplified sterile inflammatory signaling. A critical unmet gap in the field is identification of a single upstream molecular node capable of synchronously coordinating both injury programs. Building upon the foundational murine experimental work published by Wu et al. (2025) defining the STAT1-miR-497-5p-HDAC7 linear signaling cascade, this Perspective advances three exclusive, integrative conceptual frameworks original to our group: (1) STAT1 functions as a convergent master transcriptional hub that epigenetically couples ferroptosis and inflammation via one unified epigenetic axis; (2) the STAT1-miR-497-5p-HDAC7 module represents a conserved universal pathogenic cassette across all solid organ ischemia-reperfusion injury (IRI); (3) a tiered tri-modal translational pipeline integrating combinatorial circulating biomarkers, selective small-molecule HDAC7/JAK inhibitors, and tissue-targeted miR-497-5p RNA therapeutics enables dual-action liver graft protection. Beyond synthesizing published mechanistic data, we reframe field-wide generic HIRI research bottlenecks into STAT1-axis-specific testable hypotheses, including compartmentalized cell-type synergistic injury loops, estrogen-driven sexual dimorphism of STAT1 epigenetic activity, and closed bidirectional feedback circuits between STAT1 and canonical IRI pathways (NF-κB, Nrf2, HIF-1α). We further outline a cell-specific knockout and single-cell transcriptomic experimental roadmap to validate our novel predictions, and contextualize near-term clinical translation of this axis for perioperative liver protection. Targeted disruption of this STAT1-centered regulatory hub represents a uniquely promising strategy to simultaneously block both ferroptotic and inflammatory liver damage, with broad translatable implications for multi-organ IRI treatment.