SERPINE2-mediated activation of JAK2/STAT3 facilitates NRF2 nuclear translocation and GCLC transcription to confer ferroptosis resistance and lenvatinib resistance in hepatocellular carcinoma - PubMed
5 hours ago
- #lenvatinib resistance
- #SERPINE2
- #ferroptosis resistance
- SERPINE2 is upregulated in hypoxic and lenvatinib-resistant HCC, correlating with poor prognosis.
- SERPINE2 activates JAK2/STAT3 signaling, leading to STAT3-NRF2 interaction and NRF2 nuclear translocation.
- NRF2 nuclear translocation increases transcription of GCLC, boosting glutathione synthesis and inhibiting ferroptosis.
- This SERPINE2-JAK2/STAT3-NRF2-GCLC axis confers resistance to both ferroptosis and lenvatinib in HCC cells.
- Inhibiting SERPINE2, STAT3, or GCLC restores ferroptosis sensitivity and re-sensitizes HCC to lenvatinib.
- Combination therapies using JAK or NRF2 inhibitors with lenvatinib show synergistic anti-tumor effects in models.
- Clinically, high SERPINE2 levels correlate with GCLC and predict worse survival in lenvatinib-resistant patients.
- Targeting this axis offers a potential therapeutic strategy to overcome lenvatinib resistance in hepatocellular carcinoma.