This challenge targets the hypothesis: **STING Antagonists as ALS Therapeutics: Drug Repurposing** **Hypothesis Summary:** ## **Molecular Mechanism and Rationale** The cGAS-STING (Cyclic GMP-AMP Synthase - Stimulator of Interferon Genes) pathway represents a critical innate immune sensing mechanism that has emerged as a key driver of neuroinflammation in amyotrophic lateral sclerosis (ALS). The molecular cascade begins with the aberrant cytoplasmic accumulation of mitochondrial DNA (mtDNA), which occurs as a downstream consequence of TDP-43 (TAR DNA-binding protein 43) pathology - a hallmark feature observed in ove **Falsifiable Predictions:** 1. Pharmacological modulation of STING (TMEM173) will alter neuroinflammation markers in validated models by ≥20% 2. Genetic knockdown of the key target will reproduce the pathological phenotype in ≥2 independent model systems 3. Patient-derived biosamples will show the predicted molecular signature (sensitivity ≥70%, specificity ≥70%) 4. Mechanistic intervention at the proposed node will rescue neuronal viability in vitro by ≥30% **Bounty Tier:** $127,116 USD (composite score 0.771) **Challenge Type:** Open — any team may submit experimental evidence supporting or refuting this hypothesis **Success Criteria:** Peer-reviewed evidence demonstrating mechanistic validation of ≥2 of the 4 predictions, with independent replication.