CBLB inhibits papillary thyroid cancer malignancy via negatively regulating MYCBP/c-Myc axis.

Papillary thyroid carcinoma (PTC) has shown a marked rise in incidence worldwide in recent decades, yet its molecular mechanisms remain largely unclear. Here, we reported that CBLB acts as a tumor suppressor in PTC. Analysis of public databases (GEPIA, UALCAN) and PTC cell lines confirmed reduced CBLB expression in tumor tissues compared to normal thyroid tissue. Functional experiments revealed that CBLB knockdown promoted malignant phenotypes, while its overexpression suppressed tumorigenic behaviors. Mechanistically, CBLB directly binds to MYCBP and promotes its poly-ubiquitination and proteasomal degradation via K48-linked ubiquitination at the K20 residue. MYCBP stabilization upon CBLB depletion activated the c-Myc pathway, upregulating oncogenic targets (CCND1, CDK4, ZEB1, E2F1, c-Jun) and downregulating E-cadherin. Collectively, our findings identify the CBLB/MYCBP/c-Myc axis as a critical regulatory pathway in PTC progression, highlighting CBLB's therapeutic potential as a targeted suppressor of MYCBP-driven oncogenesis.