HSPA6 Confers Lenvatinib Resistance in Hepatocellular Carcinoma by Promoting Phase Separation-Mediated TXNRD1 Stabilization to Suppress Ferroptosis.

HSPA6 promotes lenvatinib resistance in hepatocellular carcinoma by stabilizing TXNRD1 through phase separation, reducing ferroptosis, and correlating with poor patient outcomes.

• Why it matters: Overcoming therapy resistance is crucial for improving long-term treatment efficacy in advanced hepatocellular carcinoma, yet the molecular mechanisms remain poorly understood.
• What they did: Using integrated multi-omics, including CRISPR screening, transcriptomics, and proteomics, the study identified HSPA6 as a key driver of resistance, showing its upregulation in resistant tumors and cell lines.
• The result: Targeting HSPA6 with repurposed canagliflozin disrupted its phase separation and resistance pathway, restoring ferroptosis sensitivity and enhancing lenvatinib effectiveness in patient-derived models.