SAD v4.0 — Public Release

VDAC1 Gate-Opening Therapeutic Stack v4.0

Public release — February 23, 2026
Registration DOI: 10.17605/OSF.IO/4KNQR
OSF Project: osf.io/yn3dw

What This Is

A mechanistically-grounded therapeutic hypothesis for microsatellite-stable (MSS) colorectal cancer targeting the VDAC1 channel on the outer mitochondrial membrane. MSS CRC is invisible to checkpoint immunotherapy (~85% of all CRC, <5% response to anti-PD-1). This framework proposes to break that silence.

The Stack

Lovastatin (strips the cholesterol lock)
  → VDAC1 oligomerizes → mtDNA escapes → cGAS-STING fires
    → Botensilimab amplifies innate → adaptive immune response

v4.0 Highlights

• Complete bench protocol for the linchpin experiment (Exp 2a/2b): lovastatin activation, mitochondrial isolation, Amplex Red cholesterol quantification, filipin staining, EGS cross-linking + Western blot for VDAC1 oligomerization. Budget: $3,010. Timeline: 4 weeks.
• Six falsifiable experiments with explicit kill conditions
• Gate-Jamming Score (GJS) equation with computational validation
• Chou-Talalay combination index analysis for dual-lock targeting
• TNBC added as fourth cancer type in the gate-opener framework
• 90-reference bibliography organized by GJS equation term
• 11 wiki pages covering every aspect of the framework

Repository Contents

• docs/SAD_v4_VDAC1_Gate_Opening_Stack.pdf — The document (22 pages)
• simulations/ — GJS simulation + Chou-Talalay calculator (Python)
• figures/ — 7 publication-quality figures
• experiments/ — Experiment index with bench protocol summary
• references/ — 90 citations + VDAC1 Pharmacology Atlas bibliography
• wiki/ — Complete documentation (11 pages)

License

CC BY-NC 4.0

What's Next

Phase B (Q2 2026): Execute Experiment 2a/2b — the linchpin. Four weeks of bench work to validate or kill the framework.