SERPINA1 drives TACE resistance in hepatocellular carcinoma by competitively binding ITGB3 to block ITCH-mediated ubiquitination and degradation

Transarterial chemoembolization (TACE) is the first-line treatment for intermediate-to-advanced hepatocellular carcinoma (HCC), but post-TACE resistance remains a major clinical challenge. While SERPINA1, a serine protease inhibitor involved in tumor microenvironment regulation, is dysregulated in various cancers, its role in TACE resistance is unclear. This study investigates SERPINA1’s functional and mechanistic involvement in HCC resistance to TACE. Serum SERPINA1 levels were measured by ELISA in TACE-treated HCC patients. Functional assays under hypoxic/chemotherapeutic conditions and xenograft models assessed tumor progression. Mechanistic studies integrated qRT-PCR, Western blot, co-immunoprecipitation (Co-IP), GST pull-down, molecular docking, and mass spectrometry to elucidate the SERPINA1-ITGB3 interaction. Elevated post-TACE serum SERPINA1 levels were significantly associated with poor treatment response and poor prognosis (P < 0.05). Functional experiments demonstrated that SERPINA1 promoted HCC cell proliferation, migration, and invasion under hypoxic and chemotherapeutic stress, while xenograft models confirmed its tumorigenic role. Mechanistically, SERPINA1 competitively bound to the EGF-like 2/3 domains of ITGB3 via its C-terminal region (amino acids 320–392), thereby shielding ITGB3 from ITCH-mediated polyubiquitination and proteasomal degradation, which consequently sustained oncogenic signaling pathways. Our study identifies the SERPINA1-ITGB3 axis as a critical mediator of TACE resistance in HCC, providing a promising therapeutic target to enhance clinical outcomes.