Sulfasalazine was recently proposed as a drug for Taxol-resistant head and neck squamous cell carcinoma (HNSCC) by inducing ferroptosis through inhibiting xCT to disrupt cystine/glutamate metabolism. However, even with low levels of PGRMC1 in normal tissues, sulfasalazine induces lipid peroxidation, highlighting potential off-target effects. Especially, postmenopausal patients are vulnerable to ferroptosis-related side effects, such as xerostomia as their hormonal changes weaken antioxidant defenses and consequently increase ROS sensitivity in salivary glands. This necessitates minimizing normal tissue damage. To address these challenges, we propose a dual-targeted drug delivery system (DDS) using cetuximab with hyaluronic acid (HA)-modified lipid nanoparticles (LNPs) as both are overexpressed in HNSCC and further overexpressed in Taxol-resistant cells. Previous studies show that HA-conjugated nanogels improve tumor targeting by sixfold in CD44/EGFR-positive cancers compared to single-target systems verifying the efficacy of suggestion. Also, LNPs enable pH-responsive drug release in acidic tumor microenvironment. By integrating dual-targeting precision with controlled release, this approach offers a novel strategy for treating Taxol-resistant HNSCC with mitigated risk of xerostomia in postmenopausal patients.