CircLAMA5 traps Sam68 in the cytoplasm to regulate alternative splicing and drive sunitinib resistance in ccRCC.

Tyrosine kinase inhibitor (TKI) resistance remains a major challenge in the treatment of clear cell renal cell carcinoma (ccRCC), yet the underlying molecular mechanisms are not fully understood. Here, we identify circular RNA circLAMA5 (hsa_circ_0061093) as a critical driver of sunitinib resistance in ccRCC. CircLAMA5 is significantly upregulated in sunitinib‑resistant cell lines and cell‑derived xenografts (CDX-R). Functional studies demonstrate that circLAMA5 enhances ccRCC cell survival, colony formation, and apoptosis evasion under sunitinib treatment both in vitro and in vivo. Mechanistically, circLAMA5 binds to the C-terminal region of Sam68 and promotes its cytoplasmic retention, at least in part by impairing the interaction between Sam68 and the nuclear import receptor TNPO1. This reduces nuclear Sam68 availability and suppresses its regulatory role in the alternative splicing of Bcl-x pre-mRNA, leading to a decreased pro‑apoptotic Bcl‑x(s)/anti‑apoptotic Bcl‑x(L) ratio and ultimately conferring sunitinib resistance. Importantly, we developed a biomimetic nanoparticle system coated with ccRCC cell membranes (RCCM@NPs) for targeted delivery of sh‑circLAMA5, effectively restoring sunitinib sensitivity in resistant tumors in vivo. Our findings reveal circLAMA5 as a key regulator of sunitinib resistance via the Sam68‑Bcl‑x splicing axis and propose a promising targeted nanotherapeutic strategy for overcoming resistance in advanced ccRCC.