ANXA1 Promotes Endoplasmic Reticulum-Mitochondria Calcium Coupling to Sustain Lenvatinib Resistance in Hepatocellular Carcinoma.

ANXA1 enhances ER-mitochondria calcium coupling by promoting contact sites, supporting lenvatinib resistance in hepatocellular carcinoma.

• Why it matters: Drug resistance limits the effectiveness of lenvatinib in treating advanced HCC, creating a critical need to understand the underlying mechanisms to improve therapy.
• What they did: The study used live-cell structured illumination microscopy and Ca2+ kinetic analysis to show that ANXA1 deficiency disrupts ER-mitochondria contact sites and reduces calcium transfer, while binding to GRP75 and ITPR1 promotes their interaction and ERMCS formation.
• The result: Targeting the ANXA1-mediated ER-mitochondria communication feedback loop resensitizes HCC to lenvatinib, inhibits angiogenesis, and improves the tumor microenvironment, suggesting a new therapeutic approach.