---
title: "Mitochondria-targeted betulinic acid derivative (Compound 14) shows antipancreatic cancer activity"
id: "pubmed-42081868"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42081868"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42081868/"
doi: "10.1016/j.bioorg.2026.109934"
published_at: "2026-08-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Mitochondria-targeted betulinic acid derivative (Compound 14) shows antipancreatic cancer activity
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42081868
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42081868/)
- **DOI:** [10.1016/j.bioorg.2026.109934](https://doi.org/10.1016%2Fj.bioorg.2026.109934)
- **Published At:** 2026-08-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Pancreatic cancer is highly lethal and often drug-resistant; betulinic acid (BA) has anticancer potential but is limited by poor solubility and lack of organelle targeting. - Investigators synthesized 30 mitochondria-targeted **betulinic acid** derivatives by conjugating delocalized lipophilic cations (DLCs), including triphenylphosphonium (TPP+), at the C-28 position of BA. - In vitro screening identified **compound 14** as the most potent against PANC-1 cells (IC50 = 1.36 ± 0.09 μM) versus BA (IC50 = 79.29 ± 6.87 μM), a ~58-fold improvement. - Transcriptomic and mechanistic studies showed compound 14 accumulates in mitochondria and induces excessive **reactive oxygen species (ROS)**, causing collapse of mitochondrial membrane potential (ΔΨm) and mitochondrial dysfunction. - Mitochondrial dysfunction triggered cytochrome c release and activation of the caspase cascade, consistent with intrinsic **mitochondrial apoptosis**. - Concurrently, compound 14 induced **ferroptosis**: upregulation of ACSL4, downregulation of GPX4, increased lipid peroxidation products, and elevated intracellular Fe2+. - The ROS scavenger N-acetylcysteine (NAC) substantially reversed ferroptosis-associated changes, supporting a ROS-dependent mechanism. - In vivo, compound 14 significantly inhibited tumor growth in xenograft models without apparent systemic toxicity. - Authors conclude compound 14 has favorable efficacy and safety in preclinical models and merits further preclinical development as a mitochondria-targeted antipancreatic cancer agent.
## Clinical Analysis & Structured Key Points
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Epub 2026 Apr 30. # Design and synthesis of mitochondria-targeted betulinic acid derivatives with antipancreatic cancer activity via ROS-mediated apoptosis and ferroptosis [Yaru Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+Y&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Yue Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Y&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Haibo Guo](https://pubmed.ncbi.nlm.nih.gov/?term=Guo+H&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Xiaofeng Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+X&cauthor_id=42081868)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-2 "People's Hospital of Ningxia Hui Autonomous, Ningxia Medical University, Yinchuan 750002, China."), [Zhaolan Ni](https://pubmed.ncbi.nlm.nih.gov/?term=Ni+Z&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Yinghan Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+Y&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Yan Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+Y&cauthor_id=42081868)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-3 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: zhaoyan@jlau.edu.cn."), [Hongbo Teng](https://pubmed.ncbi.nlm.nih.gov/?term=Teng+H&cauthor_id=42081868)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#full-view-affiliation-4 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: 13614431169@163.com.") Affiliations Expand ### Affiliations * 1 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China. * 2 People's Hospital of Ningxia Hui Autonomous, Ningxia Medical University, Yinchuan 750002, China. * 3 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: zhaoyan@jlau.edu.cn. * 4 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: 13614431169@163.com. * PMID: **42081868** * DOI: [ 10.1016/j.bioorg.2026.109934 ](https://doi.org/10.1016/j.bioorg.2026.109934) Item in Clipboard # Design and synthesis of mitochondria-targeted betulinic acid derivatives with antipancreatic cancer activity via ROS-mediated apoptosis and ferroptosis Yaru Zhao et al. Bioorg Chem. 2026. Show details Display options Display options Format Abstract PubMed PMID Bioorg Chem Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bioorg+Chem%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Bioorg+Chem%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42081868/) . 2026 Aug 5:177:109934. doi: 10.1016/j.bioorg.2026.109934. Epub 2026 Apr 30. ### Authors [Yaru Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+Y&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Yue Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Y&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Haibo Guo](https://pubmed.ncbi.nlm.nih.gov/?term=Guo+H&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Xiaofeng Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+X&cauthor_id=42081868)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-2 "People's Hospital of Ningxia Hui Autonomous, Ningxia Medical University, Yinchuan 750002, China."), [Zhaolan Ni](https://pubmed.ncbi.nlm.nih.gov/?term=Ni+Z&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Yinghan Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+Y&cauthor_id=42081868)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-1 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China."), [Yan Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+Y&cauthor_id=42081868)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-3 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: zhaoyan@jlau.edu.cn."), [Hongbo Teng](https://pubmed.ncbi.nlm.nih.gov/?term=Teng+H&cauthor_id=42081868)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42081868/#short-view-affiliation-4 "College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: 13614431169@163.com.") ### Affiliations * 1 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China. * 2 People's Hospital of Ningxia Hui Autonomous, Ningxia Medical University, Yinchuan 750002, China. * 3 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: zhaoyan@jlau.edu.cn. * 4 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin Province 130118, China; International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin Province 130118, China. Electronic address: 13614431169@163.com. * PMID: **42081868** * DOI: [ 10.1016/j.bioorg.2026.109934 ](https://doi.org/10.1016/j.bioorg.2026.109934) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract **Background:** Pancreatic cancer is a highly lethal malignancy that is frequently accompanied by drug resistance. Betulinic acid (BA) has therapeutic potential; its clinical utility is hampered by poor solubility and a lack of organelle-specific targeting. Given the functional abnormalities of tumor mitochondria, mitochondria-targeted interventions may enhance therapeutic efficacy while reducing systemic toxicity. **Methods:** Using BA as the parent scaffold, we designed and synthesized 30 mitochondria-targeted BA derivatives by attaching delocalized lipophilic cations (DLCs), including triphenylphosphonium (TPP+), at the C-28 position. We performed in vitro activity screening, transcriptomic analysis, mechanistic validation, and in vivo efficacy and safety assessments. **Results:** Compound 14 showed the strongest cytotoxicity against PANC-1 cells (IC50 = 1.36 ± 0.09 μM), which was markedly superior to BA (IC50 = 79.29 ± 6.87 μM) with a fold reduction of approximately 58. Transcriptomics and mechanistic analysis indicate that compound 14 accumulated in mitochondria, inducing excessive ROS production, which then led to the collapse of mitochondrial membrane potential (ΔΨm) and mitochondrial dysfunction. This mitochondrial dysfunction subsequently promoted cytochrome c release and activated the caspase cascade, thereby triggering intrinsic mitochondrial apoptosis. Concurrently, compound 14 induced ferroptosis by upregulating ACSL4 and downregulating GPX4, which was accompanied by increased lipid peroxidation products and intracellular Fe2+. The ROS scavenger N-acetylcysteine significantly reversed these ferroptosis-associated changes. In vivo, compound 14 significantly inhibited tumor growth in xenografts without evident systemic toxicity. **Conclusion:** Compound 14, a mitochondria-targeted BA derivative, inhibits pancreatic cancer via ROS-driven mitochondrial apoptosis and ferroptosis, showing favorable efficacy and safety and potential for preclinical development. **Keywords:** Apoptosis; Betulinic acid; Compound 14; Ferroptosis; Mitochondria-targeting; Pancreatic cancer. Copyright © 2026 Elsevier Inc. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ A potential novel treatment strategy for breast cancer: The regulation of apoptosis and metastasis by mitochondria-targeted lupeol-triphenylphosphine derivatives. ](https://pubmed.ncbi.nlm.nih.gov/41223589/) Liu X, Yang J, Song X, Zhang H, Wang Z, Ma J, Guo L, Du X, Cui H.Liu X, et al.Bioorg Chem. 2025 Dec;167:109214. doi: 10.1016/j.bioorg.2025.109214. Epub 2025 Nov 9.Bioorg Chem. 2025.PMID: 41223589 * [ Design, synthesis, and in vitro and in vivo biological evaluation of dihydroartemisinin derivatives as potent anti-cancer agents with ferroptosis-inducing and apoptosis-activating properties. ](https://pubmed.ncbi.nlm.nih.gov/39488969/) Xu Q, Deng H, Huang X, Chen GQ, Quan YS, Wang YL, Liu JY, Yan R, Nie WZ, Shen QK, Quan ZS, Guo HY.Xu Q, et al.Eur J Med Chem. 2025 Jan 5;281:117018. doi: 10.1016/j.ejmech.2024.117018. Epub 2024 Oct 30.Eur J Med Chem. 2025.PMID: 39488969 * [ Synthesis and antitumor effects of novel betulinic acid derivatives bearing electrophilic moieties. ](https://pubmed.ncbi.nlm.nih.gov/39756343/) Cai S, Guo X, Yang H, Zhao T, Li Y, Deng N, Gao Z, Meng Q, Li X, Wang S.Cai S, et al.Bioorg Med Chem. 2025 Mar 1;119:118062. doi: 10.1016/j.bmc.2025.118062. Epub 2025 Jan 3.Bioorg Med Chem. 2025.PMID: 39756343 * [ Jianpi Huayu decoction exerts antitumor effects in pancreatic cancer via SCD1-mediated lipid metabolism remodeling/ferroptosis axis. ](https://pubmed.ncbi.nlm.nih.gov/41101075/) Chen X, Ren Y, Yao R, Liu S, Fang C, Luo R, Shi H, Zhu X, Lai Y, Zhao X, Zhong C.Chen X, et al.Phytomedicine. 2025 Nov 25;148:157389. doi: 10.1016/j.phymed.2025.157389. Epub 2025 Oct 8.Phytomedicine. 2025.PMID: 41101075 * [ Facile Synthesis of Ureidic Derivatives of Betulinic Acid With Antiproliferative Effects on Colorectal and Prostate Cancer Cells. ](https://pubmed.ncbi.nlm.nih.gov/40025637/) Amin H, Kaur G, Goswami A, Bhat KA.Amin H, et al.Chem Biodivers. 2025 Jul;22(7):e202402669. doi: 10.1002/cbdv.202402669. Epub 2025 Mar 15.Chem Biodivers. 2025.PMID: 40025637Review. 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