Data for:" A nuclear-to-mitochondria adaptive circuit antagonizes ferroptosis"

Description

Although ferroptosis susceptibility is fundamentally governed by redox homeostasis, the regulatory influence of nuclear stress response pathways remains poorly defined. Here, we report that the ubiquitin-like protein ISG15 executes a previously unrecognized anti-ferroptotic role within the nucleus. Upon ferroptotic insult, CSNK1A1 mediates the dephosphorylation and subsequent nuclear import of unconjugated ISG15. Nuclear ISG15 functions not as a canonical post-translational modifier but as a transcriptional co-regulator. We delineate a redox-sensitive molecular interface through which nuclear ISG15 interacts with the oxidized form of the transcription factor YY1. This selective partnership drives the targeted transcriptional upregulation of ATP5MC1, a gene encoding a critical subunit of the mitochondrial ATP synthase complex. The ISG15–YY1–ATP5MC1 axis safeguards mitochondrial ATP synthase assembly, thereby preventing pathological mitochondrial hyperpolarization and curtailing the lethal accumulation of reactive oxygen species. Clinically, nuclear ISG15 is prevalent in human lung adenocarcinoma (LUAD) and serves as a biomarker of intrinsic ferroptosis resistance. Therapeutic targeting of the ISG15 pathway potently sensitizes tumors to ferroptosis in vivo. Collectively, our work elucidates a stress-adaptive signaling circuit that originates in the nucleus to preserve mitochondrial fitness and limit ferroptosis, nominating ISG15 as a compelling therapeutic target for overcoming ferroptosis resistance in cancer.

Institutions

• Shanghai Jiao Tong University

  Shanghai, Shanghai

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