biostudies-literatureZeng QCAS &quot;Light of West China&quot;Yunnan Fundamental Research ProjectsNational Key R&amp;D Program of Chinathe Outstanding Innovative Research Team for Molecular Enzymology and Detection in Anhui Provincial UniversitiesNational Key R&D Program of ChinaTechnology Talent and Platform Plan of Yunnan ProvinceCAS "Light of West China"National Natural Science Foundation of ChinaAcademician Expert Workstation of Yunnan Kunming126https://www.ebi.ac.uk/biostudies/studies/S-EPMC12930748biostudies-literatureUnknown24(1)<h4>Background</h4>Cholangiocarcinoma (CCA) remains a highly lethal malignancy with a dismal prognosis, primarily driven by therapeutic resistance. A dominant resistance mechanism involves overexpression of anti-apoptotic BCL-2 proteins (BCL-XL, BCL-2, MCL-1). While direct inhibition of these proteins shows efficacy, its clinical utility is frequently limited by dose-dependent hematotoxicity-as exemplified by ABT263, a BCL-XL/BCL-2 dual inhibitor that induces severe thrombocytopenia.<h4>Methods</h4>We performed integrated analyses of BCL-2 family mRNA/protein expression in clinical CCA specimens and preclinical cell lines. Leveraging proteolysis-targeting chimera (PROTAC) technology, we investigated the therapeutic application of BCL-XL-specific degraders, both as monotherapy and in combination with gemcitabine, to selectively target CCA cells while minimizing hematologic toxicity.<h4>Results</h4>Integrated clinical-experimental data identified BCL-XL as a principal determinant of therapeutic sensitivity in CCA. In vitro, the cereblon (CRBN)-based PROTAC XZ739 demonstrated superior efficacy to its von Hippel-Lindau tumor suppressor (VHL)-based counterpart DT2216, reducing CCA cell viability via apoptosis induction. In vivo, XZ739 synergized with gemcitabine to suppress tumor growth in a CCA xenograft model, achieving robust efficacy without significant thrombocytopenia-a critical advance over conventional BCL-XL inhibitors.<h4>Conclusions</h4>These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.BMC medicineTargeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma.PMC12930748821715582023YFC360330022277131YSZJGZZ-2022063202305AF150160202305AH340006xbzg-zdsys-2023122022AH010012Yang JZeng QPan YDong XZhu GLiu XLai XLuo QYang YHe YZhang YZhang XHu LZhang AfalseTargeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma.<h4>Background</h4>Cholangiocarcinoma (CCA) remains a highly lethal malignancy with a dismal prognosis, primarily driven by therapeutic resistance. A dominant resistance mechanism involves overexpression of anti-apoptotic BCL-2 proteins (BCL-XL, BCL-2, MCL-1). While direct inhibition of these proteins shows efficacy, its clinical utility is frequently limited by dose-dependent hematotoxicity-as exemplified by ABT263, a BCL-XL/BCL-2 dual inhibitor that induces severe thrombocytopenia.<h4>Methods</h4>We performed integrated analyses of BCL-2 family mRNA/protein expression in clinical CCA specimens and preclinical cell lines. Leveraging proteolysis-targeting chimera (PROTAC) technology, we investigated the therapeutic application of BCL-XL-specific degraders, both as monotherapy and in combination with gemcitabine, to selectively target CCA cells while minimizing hematologic toxicity.<h4>Results</h4>Integrated clinical-experimental data identified BCL-XL as a principal determinant of therapeutic sensitivity in CCA. In vitro, the cereblon (CRBN)-based PROTAC XZ739 demonstrated superior efficacy to its von Hippel-Lindau tumor suppressor (VHL)-based counterpart DT2216, reducing CCA cell viability via apoptosis induction. In vivo, XZ739 synergized with gemcitabine to suppress tumor growth in a CCA xenograft model, achieving robust efficacy without significant thrombocytopenia-a critical advance over conventional BCL-XL inhibitors.<h4>Conclusions</h4>These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.2026-01-01T00:00:00Z2026 Jan2026-07-09T12:24:29.731Z2026-07-09T11:17:49.502ZS-EPMC129307484161832910.1186/s12916-026-04671-9