【】 Objective This study aims to examine how gambogic acid (GA) modulates the sensitivity of pancreatic cancer cells to gemcitabine (GEM) chemotherapy, and to elucidate the underlying molecular mechanisms involved. Methods Gemcitabine-resistant pancreatic cancer cell lines were established using a concentration-escalation method. We assessed GA"s suppressive activity against drug-resistant cell proliferation. The influence of gambogic acid on leucine-rich repeat-containing protein 8A (LRRC8A)expression was examined via RT-PCR and Western blot analyses. The LRRC8A-knockdown patient-derived organoids (PDOs) model was constructed, and the half-maximal inhibitory concentration (IC50) of GEM post-knockdown was measured using the Cell Titer-Glo luminescence assay to explore the synergistic effect of GA combined with GEM on cell viability. Potential targets through which GA mitigates chemoresistance were forecasted using network-based pharmacological approaches and molecular docking simulations, with subsequent Western blot analyses providing experimental verification. To monitor GA"s therapeutic impact on neoplastic growth, murine xenograft models bearing human pancreatic carcinoma were established. Comparative immunohistochemical (IHC) analysis of LRRC8A expression levels was conducted pre- and post-intervention. Results GA significantly inhibited the growth of gemcitabine-resistant pancreatic cancer cells and PDOs (P<0.01) and effectively enhanced cellular sensitivity to GEM by regulating the LRRC8A/STAT3 signaling pathway (P<0.01). In vivo experiments further confirmed that GA intervention markedly reduced LRRC8A expression (P<0.01) and suppressed pancreatic cancer progression (P<0.01). Conclusion GA-mediated downregulation of LRRC8A confers gemcitabine sensitivity upon pancreatic cancer cells.