Transcription Factor Ets-1 Is a Central Regulator of Redox Balance and Liver Regeneration Through epidermal growth factor (EGF) and transforming growth factor-β (TGF-β) 1 Signaling.

PURPOSE: The transcription factor Ets-1 is widely implicated in hepatic carcinogenesis, yet its precise role in balancing fibrogenesis and regeneration remains poorly defined. This study elucidated the clinical relevance, upstream regulatory mechanisms, and dual cytoprotective/antifibrotic functions of Ets-1 during chronic liver injury and repair.

MATERIALS AND

METHODS

Ets-1 networks were evaluated using human cirrhotic tissues adjacent to hepatocellular carcinoma, a rat carbon tetrachloride fibrosis/recovery model, and Ets-1 knockout mice. Upstream regulation and epigenetic gating were characterized in vitro across human hepatocellular carcinoma lines via Western blotting, real-time reverse-transcription PCR, methylation-specific PCR, chromatin immunoprecipitation, and enzyme-linked immunosorbent assay.

RESULTS

Hepatic Ets-1 expression was profoundly depleted in human and rodent fibrosis, inversely correlating with disease severity, but rebounded robustly during regeneration, colocalizing with hepatocellular heme oxygenase-1 (HO-1). Ets-1 knockout mice exhibited exacerbated fibrosis, blunted HO-1 induction, and heightened injury markers under toxic stress. Mechanistically, in vitro analyses identified Ets-1 as a downstream effector of the proregenerative epidermal growth factor/extracellular signal-regulated kinase axis. Crucially, Ets-1 responsiveness to mitogens was restricted by promoter DNA hypermethylation, acting as an epigenetic gatekeeper in specific cell lines. Functionally, Ets-1 overexpression suppressed profibrogenic transforming growth factor beta 1 secretion and mitigated oxidative cytotoxicity via redox-sensitive recruitment to the HO-1 promoter. This significantly reduced macromolecular damage, as evidenced by attenuated 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine adduct formation.

CONCLUSIONS

Ets-1 acts as a pivotal molecular switch that integrates growth factor signaling with antioxidant defenses to facilitate hepatic recovery. Restoring Ets-1-mediated cytoprotection offers a potential therapeutic strategy for chronic liver disease, provided that tumorigenic risks are carefully managed via targeted hepatocyte-specific delivery systems.