HDAC6 promotes osimertinib resistance evolution in non-small cell lung cancer by activating EGFR degradation through the ubiquitin-proteasome pathway

• An in vitro osimertinib resistance evolution model was established using continuous high-dose drug induction, yielding cell lines with permanent resistance. • HDAC6 is significantly upregulated in osimertinib-resistant cells, and its knockdown or pharmacological inhibition restores drug sensitivity. • Overexpression of HDAC6 in sensitive cells reduces drug efficacy and accelerates resistance onset. • HDAC6 promotes osimertinib resistance by enhancing EGFR degradation via the ubiquitin-proteasome pathway, suggesting HDAC6 as a potential therapeutic target.