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Since it is often not diagnosed early, it typically becomes resistant to chemotherapy, and genetic alterations in tumors are associated with metabolic remodeling, inflammatory reactions, and immunological evasion. Systemic therapies have improved yet sustained responses in progressive GI disease have not been obtained and require mechanism\u2010directed approaches. Betulinic acid (BA) is an anticancer agent with low normal cell toxicity that exhibits selectivity and is obtained naturally as a pentacyclic triterpenoid. Preclinical results show that BA induces mitochondrial apoptosis, inhibits the PI3K\/Akt and NF\u2010\u03baB pathways, inhibits epithelial\u2010mesenchymal transition, and reverses cancer stemness, thereby creating resistance. There are comparative data in favor of pancreatic and colorectal cancers, with strong, validated, and effective data from aggressive disease models; data on gastric cancer accumulate through inflammation and by regulating stemness; esophageal data are preliminary. Nano\u2010delivery is the answer to BA's low solubility and bioavailability, but it still faces challenges related to scale, long\u2010term safety, and regulation. In fact, translational gaps are more about formulation than efficacy, providing a path to optimization, stratification, and clinical progress in GI cancers.<\/jats:p>","DOI":"10.1002\/mnfr.70516","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T09:07:15Z","timestamp":1781773635000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Betulinic Acid in Gastrointestinal Cancers: Mechanistic Prioritization, Nano\u2010Enabled Delivery, and Translational Barriers"],"prefix":"10.1002","volume":"70","author":[{"given":"Ajay","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Environmental Science Graphic Era (Deemed to Be University)  Dehradun Uttarakhand India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Amita","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy Guru Jambheshwar University of Science &amp; Technology  Hisar Haryana India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brahmjot","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Guru Nanak Dev University  Amritsar Punjab India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Microbiology Guru Nanak Dev University  Amritsar Punjab India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Basic and Applied Sciences Madhav University Pindwara Rajasthan India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"e_1_2_21_2_1","doi-asserted-by":"publisher","DOI":"10.5114\/pg.2024.141834"},{"key":"e_1_2_21_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2022.02.007"},{"key":"e_1_2_21_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01851-y"},{"key":"e_1_2_21_5_1","doi-asserted-by":"publisher","DOI":"10.15171\/apb.2017.041"},{"key":"e_1_2_21_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.23206"},{"key":"e_1_2_21_7_1","doi-asserted-by":"publisher","DOI":"10.21873\/invivo.11349"},{"key":"e_1_2_21_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/jfbc.13278"},{"key":"e_1_2_21_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111990"},{"key":"e_1_2_21_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2019.03.033"},{"key":"e_1_2_21_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms9061096"},{"key":"e_1_2_21_12_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2018.4604"},{"key":"e_1_2_21_13_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S493489"},{"key":"e_1_2_21_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24020355"},{"key":"e_1_2_21_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molliq.2017.04.051"},{"key":"e_1_2_21_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.13570"},{"key":"e_1_2_21_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2022.2089296"},{"key":"e_1_2_21_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodres.2025.115947"},{"key":"e_1_2_21_19_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867053202214"},{"key":"e_1_2_21_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21353"},{"key":"e_1_2_21_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28155715"},{"key":"e_1_2_21_22_1","doi-asserted-by":"crossref","unstructured":"P. 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