2. Academic Validation
  3. Bufotalin targets COL1A1 to suppress non-small cell lung cancer growth and remodel the tumor microenvironment via dual inhibition of PI3K/AKT/mTOR and MAPK pathways

Bufotalin targets COL1A1 to suppress non-small cell lung cancer growth and remodel the tumor microenvironment via dual inhibition of PI3K/AKT/mTOR and MAPK pathways

  • Eur J Pharmacol. 2026 Feb 15:1015:178601. doi: 10.1016/j.ejphar.2026.178601.
Yuxiu Zhang 1,  Panpan Lei 2,  Jinna Liang 3,  Sifan Xie 4,  Xiaoyu Ma 5,  Weina Ma 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, China. Electronic address: [email protected].
  • 2 School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, China. Electronic address: [email protected].
  • 3 Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Electronic address: [email protected].
  • 4 School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, China. Electronic address: [email protected].
  • 5 School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, China. Electronic address: [email protected].
PMID: 41581717 DOI: 10.1016/j.ejphar.2026.178601
Abstract

Non-small cell lung Cancer (NSCLC) remains the leading contributor to Cancer mortality, and its relentless progression is partly fueled by the overexpression of α1-type I Collagen (COL1A1), an extracellular-matrix protein whose abundance herald dismal prognosis and shorter survival. Here, we establish COL1A1 as a bona fide oncogenic driver: genetic silencing attenuates NSCLC proliferation and migratory capacity, whereas enforced expression accelerates both phenotypes. Exploiting this vulnerability, we identify bufotalin (BT), a bufadienolide extracted from the traditional remedy Chansu, as a selective and potent inhibitor of COL1A1-high NSCLC. BT physically engages COL1A1, triggering its post-transcriptional down-regulation and concomitantly crippling malignant fitness. Mechanistically, BT simultaneously disables the PTEN/Akt/mTOR and Ras/MEK/ERK cascades, enforces G2-M arrest via Cyclin B1/CDK1 dysregulation, and quells epithelial-to-mesenchymal transition by restoring E-cadherin while repressing N-Cadherin, MMP3, and MMP9. Beyond tumoricidal action, BT reshapes the tumor microenvironment: it suppresses TGF-β secretion, deactivates cancer-associated fibroblasts (CAFs), and severs the pro-tumorigenic COL1A1-integrin α11(ITGA11) paracrine circuit. Notably, COL1A1 reconstitution rescues CAF-induced tumor progression, underscoring COL1A1 dependency. Collectively, our findings position BT as a first-in-class COL1A1 antagonist that exerts dual cytotoxic and microenvironment-normalizing effects, providing a rational therapeutic avenue for NSCLC.

Keywords

Bufotalin; Collagen type I alpha 1; Non-small cell lung cancer; Tumor microenvironment.

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