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Solasonine (SS), a bioactive steroidal alkaloid derived from\n                    <jats:italic>Solanum nigrum<\/jats:italic>\n                    L, exhibits antitumor activity in multiple cancers, but its role in GBC and association with ferroptosis remains unknown. The purpose of this study is to investigate the therapeutic effects of SS on GBC and its underlying mechanisms using both in\u00a0vitro and in\u00a0vivo models. The efficacy was tested in subcutaneous models. Then, the anti\u2010GBC effects of SS were assessed via CCK\u20108, colony formation, and EdU assays. Biosafety was evaluated using L\u20102F7 cells and murine serum biomarkers. RNA sequencing identified key pathways, validated by ChIP\u2010qPCR and dual\u2010luciferase reporter assays. Ferroptosis induction was confirmed by measuring MDA, GSH, ROS, Fe2+, qRT\u2010PCR\/Western blot (GPX4\/SLC7A11), and rescue experiments. Direct binding of SS to APT2 was demonstrated through molecular docking, CETSA, and SPR. The study employed orthotopic xenograft models, transwell assays, and wound healing assays to investigate the effects of SS on the metastasis of GBC. SS triggered ferroptosis in GBC by elevating MDA, ROS, and Fe2+ while depleting GSH and downregulating GPX4\/SLC7A11. Mechanistically, SS directly bound APT2, inhibiting its enzymatic activity and blocking STAT3 depalmitoylation. This prevented p\u2010STAT3 nuclear translocation, suppressing transcription of ferroptosis inhibitors GPX4 and SLC7A11. In\u00a0vivo, SS suppressed tumor growth by subcutaneous and orthotopic models with no systemic toxicity. Our findings reveal SS as a novel APT2\u2010targeted ferroptosis inducer that inhibits GBC progression via inhibiting the depalmitoylation process of STAT3, providing a safe and effective therapeutic candidate for this intractable malignancy.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70245","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T23:02:01Z","timestamp":1769641321000},"page":"1642-1660","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacological Inhibition of\n                    <scp>APT2<\/scp>\n                    by Solasonine Promotes Ferroptosis Through Palmitoylation Modulation in Gallbladder Cancer"],"prefix":"10.1002","volume":"40","author":[{"given":"Liu\u2010qing","family":"Shi","sequence":"first","affiliation":[{"name":"Laboratory of General Surgery and Department of General Surgery Xinhua Hospital Affiliated With Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory of Biliary Tract Disease Research  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8653-7948","authenticated-orcid":false,"given":"Jing\u2010wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of General Surgery and Department of General Surgery Xinhua Hospital Affiliated With Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory of Biliary Tract Disease Research  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010yun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of General Surgery and Department of General Surgery Xinhua Hospital Affiliated With Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory of Biliary Tract Disease Research  Shanghai 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