CircFAM65A/CANX Condensates Sequester FAM134B to Inhibit ER‐phagy and Suppress Hepatocellular Carcinoma Progression

ER-phagy has been implicated in tumor progression; however, its regulatory mechanisms in hepatocellular carcinoma (HCC) remain largely unexplored. Here, we identified circFAM65A as a novel circRNA that is downregulated in HCC and its overexpression suppressed HCC progression. Mechanistically, circFAM65A interacted with CANX and attenuated the CANX-mediated promotion of ER-phagy and HCC progression. Specifically, circFAM65A promoted CANX condensate formation, and these condensates sequestered FAM134B, reducing the FAM134B-LC3 interaction and suppressing ER-phagy. Furthermore, a biomimetic membrane-coated nanoparticle (PLGA/circFAM65A@M-3E11) was designed to deliver circFAM65A, which effectively inhibited HCC growth in vivo. Together, these findings identify circFAM65A as a regulator of CANX-mediated ER-phagy and support its delivery as a potential therapeutic strategy for HCC.