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.

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.