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Synthetic lethality (SL) strategy may provide other targets of KRAS. Therefore, we aim to identify and validate potential therapeutic targets of KRAS for the treatment of BTC via SL.Methods: The dependency (DepMap) projects were used to predict the synthetic lethal gene of KRAS. FDA-approved anticancer drug library was applied to screen potential drugs effective against &lt;i&gt;KRAS&lt;\/i&gt;-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using &lt;i&gt;KRAS&lt;\/i&gt;-mutant and &lt;i&gt;KRAS&lt;\/i&gt;-wild type BTC cell lines, patient-derived xenografts (PDX), and &lt;i&gt;KRAS&lt;\/i&gt; oncogene-driven tumor models, as well as other &lt;i&gt;KRAS&lt;\/i&gt;-mutant cancer cell lines.Results: Initially, we discovered that the loss of GATA2 reduced the viability of &lt;i&gt;KRAS&lt;\/i&gt;-mutant but not &lt;i&gt;KRAS&lt;\/i&gt;-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1\u03b2 (IL-1\u03b2) in &lt;i&gt;KRAS&lt;\/i&gt;-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1\u03b2 to promote NF-\u03baB signaling in &lt;i&gt;KRAS&lt;\/i&gt;-mutant BTC. IL-1\u03b2 inhibition phenocopied GATA2 deficiency, leading to reduced &lt;i&gt;KRAS&lt;\/i&gt;-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a &lt;i&gt;KRAS&lt;\/i&gt; oncogene-driven tumor model, as well as in other &lt;i&gt;KRAS&lt;\/i&gt;-mutant cancer cell lines.Conclusions: In summary, these results indicate that inhibiting GATA2\/IL1\u03b2 could be a therapeutic strategy in &lt;i&gt;KRAS&lt;\/i&gt;-mutant BTC and potentially other cancers.<\/jats:p>","DOI":"10.3350\/cmh.2025.1278","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:15:53Z","timestamp":1771564553000},"page":"904-918","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-1\u03b2 as target to induce synthetic lethality in KRAS mutant biliary tract 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