Betulinic Acid in Gastrointestinal Cancers: Mechanistic Prioritization, Nano-Enabled Delivery, and Translational Barriers.

Gastrointestinal (GI) cancers are one of the leading causes of cancer death in the world. 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-directed 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-κB pathways, inhibits epithelial-mesenchymal 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-delivery is the answer to BA's low solubility and bioavailability, but it still faces challenges related to scale, long-term 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.