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Organoids, which provide a culture system that more closely resembles tumor cell organization than traditional cell lines, can be established from surgical specimens with a high success rate and are widely used for drug sensitivity assays. In this study, we aimed to identify a novel biomarker for predicting multidrug resistance using gastric cancer organoids (GCOs). We evaluated 5\u2010fluorouracil or oxaliplatin\u2010resistant GCOs to find novel biomarkers that reflect multidrug resistance in gastric cancer. To examine the resistance mechanisms, RNA\u2010sequencing analysis and\n                    <jats:italic>ex vivo<\/jats:italic>\n                    drug sensitivity testing were performed. The association of biomarkers with patient prognosis and chemotherapy efficacy was evaluated using three original cohorts with a total of 230 cases. The results were also validated with two independent public cohorts and single\u2010cell RNA sequence data. Increased expression of peptidase inhibitor 3 (\n                    <jats:italic>PI3<\/jats:italic>\n                    ) was detected in all 5\u2010fluorouracil or oxaliplatin\u2010resistant GCOs. Our findings suggest a potential association of\n                    <jats:italic>PI3<\/jats:italic>\n                    expression with ribosome biosynthesis and RNA metabolism under organoid conditions. We also found that\n                    <jats:italic>PI3<\/jats:italic>\n                    overexpression promoted 5\u2010fluorouracil\/oxaliplatin\/cisplatin resistance but not paclitaxel resistance. Immunohistochemical evaluation of PI3 expression revealed that the PI3\u2010positive gastric cancer group had a poorer outcome, especially in terms of time to recurrence. PI3 positivity was also an independent predictor of relapse after chemotherapy with DNA\u2010damaging agents.\n                    <jats:italic>PI3<\/jats:italic>\n                    promotes DNA\u2010damaging drug resistance through multiple downstream regulations related to RNA and ribosomal metabolism.\n                    <jats:italic>PI3<\/jats:italic>\n                    may be useful as a biomarker for the therapeutic selection of non\u2010DNA\u2010damaging agents. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  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