<p>To overcome resistance to MEK inhibitors such as selumetinib in neurofibroma, we developed a metabolism-targeted nanotherapeutic based on a pH-responsive silver nanoparticle platform (AgNP-PEG-TC) for delivering Triacsin C (TC), an inhibitor of long-chain acyl-CoA synthetases, to disrupt tumor-associated lipid metabolism. AgNP-PEG-TC was synthesized and characterized for its physicochemical properties, drug-loading efficiency, and pH-responsive release behavior. Its antitumor effects were assessed in human neurofibroma cells, including selumetinib-resistant cells, and in normal Schwann cells by examining proliferation, apoptosis, migration, and invasion. In vivo therapeutic efficacy and biosafety were evaluated in neurofibroma xenograft models. Bulk RNA sequencing, lipidomics, and protein analyses were performed to investigate the underlying mechanisms. AgNP-PEG-TC demonstrated stable colloidal properties and successful pH-sensitive release. It selectively reduced neurofibroma cell growth, migration, and invasion while promoting apoptosis, with minimal effects on normal cells. In xenograft models, AgNP-PEG-TC significantly inhibited tumor growth and showed good biocompatibility. Multi-omics analyses indicated that its antitumor activity was associated with ACSL4 downregulation, remodeling of arachidonic-acid-enriched phospholipids, enhanced lipid peroxidation, and increased lipid-droplet accumulation, suggesting heightened ferroptosis susceptibility. Notably, AgNP-PEG-TC synergized with MEK inhibitors and restored antitumor responses in resistant neurofibroma cells. These findings establish a metabolism-nanotechnology synergy in which AgNP-PEG-TC-mediated ACSL4 inhibition and lipid metabolic reprogramming resensitize MEK inhibitor-resistant neurofibromas to therapy. The platform functions as both a targeted drug carrier and a modulator of tumor lipid homeostasis, offering a promising combinatorial strategy.</p> Graphical abstract <p></p>